WO2024015331A1 - Therapeutic and diagnostic methods for multiple sclerosis - Google Patents

Therapeutic and diagnostic methods for multiple sclerosis Download PDF

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Publication number
WO2024015331A1
WO2024015331A1 PCT/US2023/027334 US2023027334W WO2024015331A1 WO 2024015331 A1 WO2024015331 A1 WO 2024015331A1 US 2023027334 W US2023027334 W US 2023027334W WO 2024015331 A1 WO2024015331 A1 WO 2024015331A1
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polymorphism
seq
allele
subject
linkage disequilibrium
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French (fr)
Inventor
Xiaoming Jia
Tushar Ramesh BHANGALE
Paola BRONSON
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Genentech Inc
Biogen Inc
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Genentech Inc
Biogen Inc
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention is directed to methods of monitoring and/or treating subjects suffering from multiple sclerosis (MS), methods of selecting a therapy for a subject suffering from MS or at risk of developing an early onset of MS, and methods of determining whether a subject is at increased risk of MS progression or at risk of developing an early onset of MS.
  • MS multiple sclerosis
  • MS Multiple sclerosis
  • PPMS primary progressive multiple sclerosis
  • RMS relapsing MS
  • SPMS secondary progressive MS
  • PMS progressive forms of MS
  • Studies have identified over 200 loci, which are largely autoimmune loci, associated with MS risk, validating the immunomodulatory mechanisms of MS therapies. While therapies are effective for suppressing MS disease activity, they are only modestly effective in preventing disability progression.
  • the present invention is directed, inter alia, to methods of monitoring and/or treating subjects suffering from MS, methods of selecting a therapy for a subject suffering from MS or at risk of developing an early onset of MS, and methods of determining whether a subject is at increased risk of MS progression and/or at risk of developing an early onset of MS.
  • the disclosure encompasses a method of treating a subject suffering from MS, the method comprising administering to the subject a therapy comprising an immunomodulatory disease-modifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of: (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphis
  • the invention features a method of determining whether a subject is at increased risk of MS progression, the method comprising determining in a sample derived from a subject suffering from MS the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of a C allele at polymorphism rs4962725 (SEQ ID NO: 1), or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), indicates that the subject has an increased risk of MS progression.
  • the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), compared to a subject whose genotype does not comprise a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1).
  • the disclosure encompasses a method of treating a subject suffering from multiple sclerosis (MS), the method comprising: (a) determining in a sample derived from a subject suffering from MS the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression, and/or (b) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject who has been identified as having an increased risk of MS progression.
  • a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject who has been identified as having an increased risk of MS progression.
  • polymorphism in linkage disequilibrium with polymorphism rs4962725 is polymorphism rslO633O91 (SEQ ID NO: 6), and the equivalent allele is an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6).
  • the risk of MS progression is in terms of rate of T2 magnetic resonance imaging lesion volume change (T2LVC).
  • the method further comprises administering an immunomodulatory disease-modifying therapeutic agent to the subject.
  • the invention features a method of determining whether a subject is at risk of developing an early onset of MS, the method comprising determining in a sample derived from the subject the genotype at one or more of: (a) polymorphism rs3129882 (SEQ ID NO: 2), wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) polymorphism rs309I826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) in a sample derived from the subject, wherein the subject is at risk of developing an early onset of MS if the genotype of the
  • the subject is at risk of developing an early onset of MS if the genotype of the subject comprises one or more of (a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), compared to a subject whose genotype does
  • polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092737 (SEQ ID NO: 4) and/or polymorphism rs3092258 (SEQ ID NO: 5), and the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the method further comprises (a) monitoring the subject who has been identified as having a risk of developing an early onset of MS for one or more symptoms of MS; (b) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and (c) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject diagnosed with MS.
  • the invention features a method of treating a subject having an increased risk of MS progression, the method comprising administering to the subject a therapy comprising an immunomodulatory disease-modifying therapeutic agent, wherein the genotype of the subject has been determined to comprise a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), indicating that the subject is at increased risk for MS progression.
  • the invention features a method of treating a subject having an increased risk of early onset of MS, the method comprising administering to the subject a therapy comprising an immunomodulatory disease-modifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of: (a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), indicating that the subject is at increased risk for early onset of MS; (b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), indicating that the subject is at increased risk for early onset of MS; (c) a T allele at polymorphism rs28672722 (SEQ ID NO: 2) or
  • the disclosure encompasses a method of treating a subject having an increased risk of early onset of MS and/or an increased risk of MS progression, the method comprising administering to the subject a therapy comprising an immunomodulatory diseasemodifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of: (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: I), indicating that the subject is at increased risk for MS progression; (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), indicating that the subject is at increased risk for early onset of MS; (c) a G allele at polymorphism
  • the invention features a method of preventing or reducing the likelihood of developing MS in a subject, the method comprising administering to the subject a therapy comprising an immunomodulatory disease-modifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of: (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism
  • the disclosure encompasses a method of preventing and/or reducing the likelihood of developing MS in a subject, the method comprising: (a) determining in a sample derived from the subject the genotype at one or more of: (i) polymorphism rs3129882 (SEQ ID NO: 2), or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS; (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826
  • the invention features a method of selecting a therapy for preventing and/or reducing the likelihood of developing MS in a subject, the method comprising: (a) determining in a sample derived from a subject the genotype at one or more of: (i) polymorphism rs3129882 (SEQ ID NO: 2), or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS;; (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism r
  • the subject is at risk of developing an early onset of MS if the genotype of the subject comprises one or more of: (a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (c) a T allele at polymorphism rs28672722 (SEQ ID NO: 9), compared to a subject whose genotype does not comprise a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (d) a T allele at polymorphism rs37411 (SEQ ID NO: 2), compared
  • the invention features a method of monitoring and/or treating a subject having a risk of developing an early onset of MS, the method comprising: (a) determining in a sample derived from a subject if the genotype of the subject comprises one or more of: (i) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS; (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs30
  • the invention features a method of treating a subject who has been previously determined to comprise one or more of (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 1) or an equivalent all
  • the invention features a method further comprising: (a) monitoring the subject who has been identified as having a risk of developing an early onset of MS for one or more symptoms of MS; (b) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and (c) administering a therapy comprising an immunomodulatory diseasemodifying therapeutic agent to the subject diagnosed with MS.
  • the invention features a method of selecting a therapy for a subject at risk of developing an early onset of MS, the method comprising: (a) determining in a sample derived from a subject the genotype at one or more of: (i) polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), indicates that the subject has a risk of developing an early onset of MS; (ii) polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 2)
  • the invention features a method further comprising: (a) monitoring the subject who has been identified as having a risk of developing an early onset of MS for one or more symptoms of MS; (b) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and (c) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject diagnosed with MS.
  • the disclosure encompasses a method of selecting a therapy for a subject suffering from MS, the method comprising: (a) determining in a sample derived from a subject suffering from MS the genotype at one or more of: (i) polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression; and/or (ii) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO:
  • the invention features an immunomodulatory disease-modifying therapeutic agent for use in a method of monitoring and treating a subject having a risk of developing an early onset of MS, the method comprising: (a) determining in a sample derived from a subject the genotype at one or more of: (i) polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS; and/or (ii) polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a
  • an immunomodulatory disease-modifying therapeutic agent for use in treating a subject suffering from MS, wherein the genotype of the subject has been determined to comprise one or more of: (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (d) a
  • an immunomodulatory disease-modifying therapeutic agent for use in a method of treating a subject suffering from MS, the method comprising: (a) determining in a sample derived from a subject suffering from MS the genotype at: (i) polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression; (ii) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2),
  • an immunomodulatory disease-modifying therapeutic agent for use in treating a subject who has who has been previously diagnosed with MS and who has been previously determined to comprise one or more of: (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), thereby indicating that the subject has an increased risk of MS progression; (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), thereby identifying the subject as having a risk of developing an early onset of MS; (c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at a polymorphism rs30918
  • an immunomodulatory disease-modifying therapeutic agent for use in preventing and/or reducing the likelihood of developing MS in a subject who has been previously determined to comprise one or more of: (a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), thereby identifying the subject as having a risk of developing an early onset of MS; and/or (b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), thereby identifying the subject as having a risk of developing an early onset of MS; and/or (c) a T allele at polymorphism rs28672722 (SEQ ID NO: 2)
  • kits for determining whether a subject is at increased risk of MS progression comprising one or more reagents for determining the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) in a sample derived from a subject, and instructions for use, wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1).
  • kits for determining whether a subject is at a risk of developing an early onset of MS comprising one or more reagents for determining the genotype at one or more of: (a) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilib
  • kits for determining whether a subject is at increased risk of MS progression and/or whether a subject is at a risk of developing an early onset of MS comprising one or more reagents for determining the genotype at one or more of: (a) polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) in a sample derived from a subject, and instructions for use, wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (b) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage
  • the invention features a kit for determining whether a subject is at increased risk of MS progression, the kit comprising and instructions for use and one or more reagents for determining the genotype in a sample derived from a subject, (a) at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); and/or (b) at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs312988
  • polymorphism in linkage disequilibrium with polymorphism rs4962725 is polymorphism rslO633O91 (SEQ ID NO: 6), and the equivalent allele is an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6).
  • polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092737 (SEQ ID NO: 4) and/or polymorphism rs3092258 (SEQ ID NO: 5), and the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the methods of the invention further comprise administering an immunomodulatory disease-modifying therapeutic agent to the subject.
  • the subject’s genotype is determined from a sample derived from the subject selected from a whole blood sample, a serum sample, a plasma sample, or a combination thereof.
  • the sample derived from the subject is a whole blood sample.
  • the immunomodulatory disease-modifying therapeutic agent is selected from an interferon beta (IFNP) agent; a monoclonal antibody (mAb); a sphingosine 1 -phosphate receptor modulator; an anthracenedione antineoplastic; a pyrimidine synthesis inhibitor; a polymer of glutamic acid, lysine, alanine, and tyrosine; a fumarate agent; and an antimetabolite.
  • IFNP interferon beta
  • mAb monoclonal antibody
  • sphingosine 1 -phosphate receptor modulator an anthracenedione antineoplastic
  • a pyrimidine synthesis inhibitor a polymer of glutamic acid, lysine, alanine, and tyrosine
  • fumarate agent and an antimetabolite.
  • the immunomodulatory disease-modifying therapeutic agent is selected from the group consisting of ocrelizumab (Ocrevus®) (Roche), fmgolimod (Gilenya®) (Novartis), dimethyl fumarate (Tecfidera®) (Biogen), diroximel fumarate (Vumerity®) (Alkermes/Biogen), teriflunomide (Aubagio®) (Genzyme), siponimod (Mayzent®) (Novartis), cladribine (Mavenclad®) (Merck), alemtuzumab (Lemtrada®) (Sanofi-Aventis), mitoxantrone (Novantrone®), and natalizumab (Tysabri®) (Biogen).
  • Ocrevus® Roche
  • fmgolimod Gavartis
  • dimethyl fumarate Tecfidera®
  • Veumerity® diroximel fumarate
  • the IFNP agent is selected from AVONEX® (interferon beta- la), BETASERON® (interferon beta-lb), EXTAVIA® (interferon beta-lb), PLEGRIDY® (peginterferon beta-la), and REBIF® (interferon beta-la).
  • the mAb is selected from KESIMPTA® (ofatumumab), LEMTRADA® (alemtuzumab), OCREVUS® (ocrelizumab), and TYSABRI® (natalizumab).
  • the sphingosine 1 -phosphate receptor modulator is selected from GILENYA® (fmgolimod), MAYZENT® (siponimod), PONVORYTM (ponesimod), and ZEPOSIA® (ozanimod).
  • the anthracenedione antineoplastic is NOVANTRONE® (mitoxantrone).
  • the pyrimidine synthesis inhibitor is AUBAGIO® (teriflunomide).
  • the polymer of glutamic acid, lysine, alanine, and tyrosine is selected from COPAXONE® (glatiramer acetate), GLATOPA® (glatiramer acetate), and Glatiramer Acetate Injection (glatiramer acetate).
  • the fumarate agent is BAFIERTAMTM (monomethyl fumarate), Dimethyl Fumarate (dimethyl fumarate), TECFIDERA® (dimethyl fumarate), or VUMERITY® (diroximel fumarate).
  • the antimetabolite is MAVENCLAD® (cladribine).
  • the invention features a method further comprising administering an additional therapeutic agent to the subject.
  • the additional therapeutic agent is a corticosteroid.
  • the additional therapeutic agent is selected from SOLU-MEDROL® (methylprednisolone) or DELTASONE® (prednisone).
  • the additional therapeutic agent is a symptom managing agent for treatment of one or more symptoms of MS.
  • the symptom is a dysfunctional bladder and the symptom managing agent is selected from BOTOX® (onabotulinumtoxin A), DDAVP Nasal Spray (desmopressin), DETROL® (tolterodine), DITROPAN® (oxybutynin), DITROPAN XL®, ENABLEX® (darifenacin), FLOMAX® (tamsulosin), Prazosin, MYRBETRIQ® (mirabegron), OXYTROL® (oxybutynin), TOFRANIL (imipramine), and VESICARE (solifenacin succinate).
  • BOTOX® onabotulinumtoxin A
  • DDAVP Nasal Spray deTROL® (tolterodine)
  • DITROPAN® oxybutynin
  • DITROPAN XL® ENABLEX® (darifenacin)
  • FLOMAX® tamsulosin
  • Prazosin tamsul
  • the symptom is a bladder infection and the symptom managing agent is selected from BACTRIM®, SEPTRA® (sulfamethoxazole), CIPO® (ciprofloxacin), LEVAQUIN® (levofloxacin), MACRODANTIM® (nitrofurantoin), HIPREX® (methenamine), and PYRIDIUM® (phenazopy ri dine) .
  • BACTRIM® sulfamethoxazole
  • CIPO® ciprofloxacin
  • LEVAQUIN® levofloxacin
  • MACRODANTIM® nitrogenantoin
  • HIPREX® metalhenamine
  • PYRIDIUM® phenazopy ri dine
  • the symptom is a bowel dysfunction and the symptom managing agent is selected from COLACE® (docusate), DULCOLAX® (bisacodyl), ENEMEEZ® (docusate stool softener laxative), FLEET ENEMA® (sodium phosphate), a mineral oil, METAMUCIL® (psyllium hydrophilic musilloid), Phillips® Milk of Magnesia (magnesium hydroxide), and Sani-Supp® suppository (glycerin).
  • COLACE® docusate
  • DULCOLAX® bisacodyl
  • ENEMEEZ® docusate stool softener laxative
  • FLEET ENEMA® sodium phosphate
  • METAMUCIL® psyllium hydrophilic musilloid
  • Phillips® Milk of Magnesia magnesium hydroxide
  • Sani-Supp® suppository glycerin
  • the symptom is depression and the symptom managing agent is an antidepressant.
  • the antidepressant is selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), a norepinephrine dopamine reuptake inhibitor (NDR1), a serotonin partial agonist and reuptake inhibitor (SPARI), a serotonin antagonist and reuptake inhibitor (SARI), a monoamine oxidase inhibitor (MAOI), a N-methyl-d-aspartic acid (NMDA) antagonist, and noradrenergic and specific serotonergic antidepressant (NASSA).
  • SSRI selective serotonin reuptake inhibitor
  • SNRI serotonin norepinephrine reuptake inhibitor
  • TCA tricyclic antidepressant
  • NDR1 norepinephrine dopamine
  • the antidepressant is selected from CELEXA® (citalopram), CYMBALTA® (duloxetine hydrochloride), EFFEXOR® (velafaxine), PAXIL® (paroxetine), PROZAC® (fluoxetine), WELLBUTRIN® (bupropion), and ZOLOFT® (sertraline).
  • the symptom is dizziness and/or vertigo and the symptom managing agent is ANTIVERT® (meclizine).
  • the symptom is pseudobulbar affect and the symptom managing agent is NUEDEXTA® (dextromethorphan and quinidine).
  • the symptom is fatigue and the symptom managing agent is selected from ADDERALL® (dextroamphetamine and amphetamine), amantadine, PRO VIGIL® (modafinil), PROZAC® (fluoxetine), and RITALIN® (methylphenidate).
  • the symptom is itching and the symptom managing agent is VISTARIL® (hydroxyzine).
  • the symptom is pain and the symptom managing agent is selected from CYMBALTA® (duloxetine), EFFEXOR® (venlafaxine), ELAVIL® (amitriptyline), LAMICTAL® (lamotrigine), LYRICA® (pregabalin), NEURONTIN® (gabapentin), PAMELOR® (nortriptyline HCL), AVENTYL® (nortriptyline), TEGETRO®L (carbamazepine), and TRILEPTAL® (oxcarbazepine).
  • the symptom is a sexual problem and the symptom managing agent is selected from CIALIS® (tadalafil), LEVITRA® (vardenafil), MUSE® (alprostadil), PROSTIN VR® (alprostadil), STENDRA® (avanafil), and VIAGRA® (sildenafil).
  • the symptom is spasticity and the symptom managing agent is selected from baclofen, BOTOX® (onabotulinumtoxin A), DANTRIUM® (dantrolene), KLONOPIN® (clonazepam), VALIUM® (diazepam), and ZANAFLEX® (tizanidine).
  • the symptom is a tremor and the symptom managing agent is selected from LANIAZID® (isoniazid) and KLONOPIN® (clonazepam).
  • the symptom is difficulty walking and the symptom managing agent is AMPYRA® (dalfampridine).
  • the MS is a clinically isolated syndrome (CIS). In some aspects, the MS is a relapsing-remitting MS (RRMS). In some aspects, the MS is a primary progressive MS (PPMS). In some aspects, the MS is a secondary progressive MS (SPMS).
  • CIS clinically isolated syndrome
  • RRMS relapsing-remitting MS
  • PPMS primary progressive MS
  • SPMS secondary progressive MS
  • FIG. 1 is a schematic illustration describing the analysis pipeline used in the experiments described in Example 2.
  • Figure 2A is a Manhattan plot for the meta-analyzed GWAS summary statistics of the three Group A cohorts and three Group B cohorts described in Example 2.
  • Figure 2B is a LocusZoom plot of top GWAS hit and nearby SNPs described in Example 2.
  • Figure 3 is a Manhattan plot for the gene-based tests of association, calculated from SNP summary statistics and p-values.
  • Figure 4A is a 2-Sample Mendelian randomization scatterplot visualization for associations between Telomere Length and MS AAO.
  • Figure 4B is a 2-Sample Mendelian randomization scatterplot visualization for associations between Age at Puberty and MS AAO.
  • the present invention in based, at least in part, on the discovery of polymorphic alleles that are associated with risk of MS progression (e.g., in terms of T2LVC) or age-at-onset (AAO) for MS.
  • polymorphic alleles that are associated with risk of MS progression (e.g., in terms of T2LVC) or age-at-onset (AAO) for MS.
  • C allele at polymorphism rs4962725 (SEQ ID NO: 1) in an intron of the C-terminal binding protein 2 (CTBP2) gene was associated with an increased risk of MS progression (e.g., in terms of rate of T2LVC).
  • One equivalent allele i.e., surrogate allele was identified to be in linkage disequilibrium with polymorphism rs4962725C: an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6).
  • Subjects having an increased risk of MS progression can be treated according to the methods disclosed herein, e.g., by administering a disease-modifying therapeutic agent (DMT), e.g., an immunomodulatory DMT, to the subject.
  • DMT disease-modifying therapeutic agent
  • an A allele at polymorphism rs3129882 (SEQ ID NO: 2) in major histocompatibility complex class II DR alpha (HLA-DRA) was associated with a decreased risk of developing an early AAO for MS; subjects with one copy of the rs3129882A allele experienced onset of MS about 1 .24 years later than subjects with the rs3129882G allele.
  • a G allele at polymorphism rs3091826 located in eyes absent homolog 2 (EYA2) was associated with an increased risk of developing an early AAO for MS; subjects with one copy of the rs3091826G allele experienced onset of MS about 3 year earlier than subjects with a rs3091826A or rs3091826T allele.
  • a T allele at polymorphism rs28672722 (SEQ ID NO: 9), or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); a T allele at polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) were associated with an earlier AAO.
  • Subjects having a risk of an early onset of MS may be prophylactically treated according to the methods disclosed herein to prevent or reduce the likelihood of developing MS, e.g., by administering a DMT, e.g., an immunomodulatory DMT, to the subject.
  • a DMT e.g., an immunomodulatory DMT
  • MS Multiple sclerosis
  • the immune system attacks the protective sheath (myelin) that covers nerve fibers and causes communication problems between the brain and the rest of the body Eventually, the disease can cause permanent damage or deterioration of the nerve fibers.
  • MS multiple sclerosis
  • Early treatment improves long-term health and wellbeing by slowing down the buildup of irreversible damage and reducing the number of relapses people experience, and therefore the ability to target treatment to patient populations having an increased risk of MS progression is highly beneficial.
  • Stages of MS there are four stages of MS: (1) Clinically isolated syndrome (CIS): This is the first episode of symptoms caused by inflammation and damage to the myelin covering on nerves in the brain or spinal cord. (2) Relapsing-remitting MS (RRMS): The relapsing-remitting type of MS generally follows a predictable pattern, with periods in which symptoms worsen and then improve. Eventually, it may progress to secondary-progressive MS. Subjects with RRMS have flare-ups (relapses) of MS, and between the relapses, they have periods of remission. (3) Secondaryprogressive MS (SPMS): RRMS can progress into a more aggressive form of the disease. Some subjects with RRMS will go on to develop SPMS.
  • SPMS Secondaryprogressive MS
  • PPMS Primary-progressive MS
  • DMTs Disease modifying therapies
  • MS Early onset of MS: Subjects of any age can develop MS, although subjects with MS tend to have their first symptoms between the ages of 20 and 40. Early detection of MS is critical as early treatment of MS can help delay progression of the disease. While the disease is chronic, it is usually mild in most case at the beginning. Elowever, some subjects may become unable to walk, have abnormal sensation and loss of balance, and the disease may also affect memory as the disease progresses. Treatment with MS medications has repeatedly shown to stop this progression. Thus, the ability to identify patient populations at risk of early onset of MS can, and then target these patient populations for treatment, is highly beneficial as early intervention and treatment can improve and prolong the quality of life of MS subjects. I. Therapeutic Methods
  • the present invention provides methods of treating a subject suffering from MS, such as CIS, RRMS, PPMS, SPMS.
  • the methods of the invention include administering a therapy (e g., an immunomodulatory DMT agent) to a subject based on the patient’s genotype at one or more genetic polymorphisms described herein (e.g., a polymorphism selected from rs4962725 (SEQ ID NO: 1); rs3129882 (SEQ ID NO: 2); rs3091826 (SEQ ID NO: 3); rs28672722 (SEQ ID NO: 9); rs37411 (SEQ ID NO: 10), and/or a polymorphism that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), rs3129882 (SEQ ID NO: 2), rs3091826 (SEQ ID NO: 3), rs28672722 (SEQ ID NO: 9), and/or
  • the rs4962725 (SEQ ID NO: 1) polymorphism is located within an intron of the C-terminal binding protein 2 (CTBP2)' gene.
  • the rs3129882 (SEQ ID NO: 2) polymorphism is located within an intron of the major histocompatibility complex class II DR alpha (HLA-DRA) gene.
  • the rs3091826 (SEQ ID NO: 3) polymorphism is located within an intron of the eyes absent homolog 2 (EYA2) gene.
  • the rs28672722 (SEQ ID NO: 9) polymorphism is located within the HLA-DQB1- AS1 gene, and the rs37411 (SEQ ID NO: 10) polymorphism is located within the LOC105375167 gene.
  • the rsl 1755689 (SEQ ID NO: 11) polymorphism is located within the HLA-DQA1 gene, and the rs28359884 (SEQ ID NO: 12) polymorphism is intergenic.
  • the disclosure provides a method of treating a subject suffering from MS, the method including administering to the subject a therapy including a DMT agent (e g., an immunomodulatory DMT agent), wherein the genotype of the subject has been determined to include one or more of (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequi
  • a DMT agent e
  • polymorphism in linkage disequilibrium with polymorphism rs4962725 is polymorphism rsl0633091 (SEQ ID NO: 6).
  • the equivalent allele is an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6).
  • the disclosure provides a method of treating a subject suffering from MS, the method including: (a) determining in a sample derived from a subject suffering from MS the genotype at one or more of (i) polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression; and/or (ii) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of
  • the polymorphism in linkage disequilibrium with polymorphism rs4962725 is polymorphism rs!0633091 (SEQ ID NO: 6).
  • the equivalent allele is an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6).
  • the disclosure features a method of preventing and/or reducing the likelihood of developing MS (e.g., an early onset of MS) for a subject, the method comprising administering to the subject a therapy comprising a DMT agent (e.g., an immunomodulatory DMT agent), wherein the genotype of the subject has been determined to comprise one or more of (a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) a T allele at polymorphism rs28672722 (SEQ ID NO:
  • the disclosure features a method of preventing and/or reducing the likelihood of developing MS in a subject (e.g., an early onset of MS), the method comprising: (a) determining in a sample derived from the subject the genotype at one or more of (i) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequi
  • the disclosure features a method of selecting a therapy for preventing or reducing the likelihood of developing MS in a subject (e.g., an early onset of MS), the method comprising: (a) determining in a sample derived from a subject the genotype at (i) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequi
  • the subject is at an increased risk of developing MS (e.g., an early onset of MS) if the genotype of the subject comprises one or more of a (a) G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), compared
  • the disclosure encompasses a method of identifying a subject at an increased risk of developing MS (e.g., an early onset of MS) if the genotype of the subject comprises one or more of a (a) G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826
  • the disclosure provides a method of treating a subject who has been previously determined to have one or more of a (a) G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (d) T allele at polymorphism rs37411 (SEQ ID NO: 10) or
  • the polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092737 (SEQ ID NO: 4).
  • the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4).
  • the polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092258 (SEQ ID NO: 5).
  • the equivalent allele is a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the disclosure provides a method of treating a subject who has been previously determined to have one or more of a (a) G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (d) T allele at polymorphism rs37411 (SEQ ID NO: 10) or
  • the polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092737 (SEQ ID NO: 4).
  • the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4).
  • the polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092258 (SEQ ID NO: 5).
  • the equivalent allele is a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the disclosure provides a method of monitoring and/or treating a subject having a risk of developing an early onset of MS, the method including: (a) determining in a sample derived from the subject the genotype at (i) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS; (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO:
  • the polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092737 (SEQ ID NO: 4).
  • the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4).
  • the polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092258 (SEQ ID NO: 5).
  • the equivalent allele is a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the present disclosure provides for methods of treating a subject (e.g., a human) with one or more (e.g., 1, 2, 3, 4, 5, 6, etc.) of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a C allele at polymorphism rs3092737 (SEQ ID NO: 4); (v) a C allele at polymorphism rs3092258 (SEQ ID NO: 5); (vi) an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6); (vii) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (viii)
  • a subject with a C allele at polymorphism rs4962725 (also referred to herein as “rs4962725C”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), e.g., an insertion of AG at polymorphism rs 10633091 (SEQ ID NO: 6) (also referred herein as “rsl0633091CAG”), is at an increased risk of MS progression (e.g., in terms of rate of T2LVC), compared to a subject whose genotype does not contain a C allele (e.g., a subject containing a T allele) at polymorphism rs4962725 (SEQ ID NO: 1), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs
  • the rs!0633091CAG allele is an insertion of an AG following the C located at chromosome (chr) 10, nucleotide position 125044448 (i.e., chrlO: 125044448), e.g., relative to Genome Reference Consortium Human Build 38 patch release 13 (GRCh38.pl3).
  • the two alleles for polymorphism rsl0633091 are CAG (i.e., an insertion of AG) and C, of which CAG is the surrogate for rs496272C.
  • nucleotide sequence of variable SEQ ID NO: 6 (e.g., when AG is absent) may be CTCTGACTTTTCATCCGGAGTTAACCCACATGTGCTCAGGCCACCTCAAA (SEQ ID NO: 7).
  • nucleotide sequence of variable SEQ ID NO: 6 (e.g., when AG is inserted) may be CTCTGACTTTTCATCCGGAGTTAACAGCCACATGTGCTCAGGCCACCTCAAA (SEQ ID NO: 8).
  • a subject with a G allele at polymorphism rs3129882 (SEQ ID NO: 2) (also referred herein as “rs3129882G”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), is at risk of developing MS, such as an early age-at-onset (AAO) of MS, compared to a subject whose genotype does not contain a G allele (e.g., a subject containing an A allele) at polymorphism rs3129882 (SEQ ID NO: 2), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2).
  • AAO early age-at-onset
  • a subject with a G allele at polymorphism rs3091826 (SEQ ID NO: 3) (also referred herein as “rs3091826G”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5), is at risk of developing MS, such as an early AAO of MS, compared to a subject whose genotype does not contain a G allele (e.g., a subject containing an A or a T allele) at polymorphism rs3091826 (SEQ ID NO: 3), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorph
  • the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6))-
  • the subject has the following genotype: a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882.
  • the subject has the following genotype: a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)).
  • a G allele at polymorphism rs3091826 SEQ ID NO: 3
  • an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e g., an insertion of AG at polymorphism rsl 0633091 (SEQ ID NO: 6)); and a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882.
  • the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5))
  • the subject has the following genotype: a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882; and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)).
  • the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882; and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO:
  • the subject has the following genotype: a T allele at polymorphism rs28672722 (SEQ ID NO: 9), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722.
  • the subject has the following genotype: a T allele at polymorphism rs37411 (SEQ ID NO: 10), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411.
  • the subject has the following genotype: a G allele at rsl 1755689 (SEQ ID NO: 11), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11).
  • the subject has the following genotype: an A allele at polymorphism rs28359884 (SEQ ID NO: 12), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
  • the subject has any one of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725
  • the subject has any two of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs49627
  • the subject has any three of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725
  • the subject has any four of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725
  • the subject has any five of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725
  • the subject has six, seven, eight, nine, or ten of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorph
  • the equivalent allele may be at an alternate single nucleotide polymorphism (SNP) that is in linkage disequilibrium with one or more of the selected SNPs described herein (e.g., rs4962725 (SEQ ID NO: 1); rs3129882 (SEQ ID NO: 2); rs3091826 (SEQ ID NO: 3)); rs28672722 (SEQ ID NO: 9); rs37411 (SEQ ID NO: 10); rsl 1755689 (SEQ ID NO: 11); and/or rs28359884 (SEQ ID NO: 12).
  • SNP alternate single nucleotide polymorphism
  • the equivalent allele that is in linkage disequilibrium with rs4962725 is an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6).
  • the equivalent allele that is in linkage disequilibrium with rs3091826 is a C allele at polymorphism rs3092737 (SEQ ID NO: 4).
  • the equivalent allele that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3) is a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the subject’s genotype may include a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the linkage disequilibrium is a D’ value or an r 2 value.
  • the D’ measure between the selected SNP and the alternate SNP is > 0.60 (e.g., > 0.60, > 0.65, > 0.7, > 0.75, > 0.8, > 0.85, > 0.9, > 0.95, or higher).
  • the D’ value between the selected SNP and the alternate SNP is >0.70, > 0.80, or > 0.90.
  • the D’ value between the selected SNP and the alternate SNP is 1.0.
  • the r 2 value between the selected SNP and the alternate SNP is > 0.60 (e.g., > 0.60, > 0.65, > 0.7, > 0.75, > 0.8, > 0.85, > 0.9, > 0.95, or higher).
  • the r 2 value between the selected SNP and the alternate SNP is > 0.70, > 0.80, or > 0.90.
  • the r 2 value between the selected SNP and the alternate SNP is 1.0.
  • the equivalent allele may be the minor allele or the major allele. In some instances, the equivalent allele is the minor allele. In other instances, the equivalent allele is the major allele.
  • the genotype of the subject is derived from a sample of the subject, such as blood, plasma, serum, urine, saliva, stool, pleural fluid, lymphatic fluid, sputum, ascites, prostatic fluid, cerebrospinal fluid (CSF), or any other bodily secretion or derivative thereof.
  • the sample derived from the subject is a whole blood sample, a serum sample, a plasma sample, or a combination thereof.
  • the sample derived from the subject is a whole blood sample.
  • the sample derived from a subject is a serum sample.
  • the sample derived from a subject a plasma sample.
  • genotype of a subject can be determined using any of the methods or assays described herein or that are known in the art.
  • the present disclosure provides for methods of treating a subject (e.g., a human) described herein with at least one DMT agent, such as any DMT agent described herein (e.g., an immunomodulatory DMT).
  • the subject may be further administered one or more additional therapeutic agents in combination with the at least one DMT agent.
  • Additional therapeutic agents such as corticosteroids and symptom managing agents, may also be administered to the subject and are described herein.
  • the methods of the invention include administering to the subject (e.g., a human) a therapy including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable DMT agent (e.g., an immunomodulatory DMT agent), such as any of the DMT agents described herein.
  • a therapy including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable DMT agent (e.g., an immunomodulatory DMT agent), such as any of the DMT agents described herein.
  • the methods of the invention include administering to the subject (e.g., a human) a combinatorial therapy including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable DMT agent (e.g., an immunomodulatory DMT agent), such as any of the DMT agents described herein, and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable corticosteroid, such as any of the corticosteroids described herein.
  • a combinatorial therapy including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable DMT agent (e.g., an immunomodulatory DMT agent), such as any of the DMT agents described herein, and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable corticosteroid, such as any of the corticosteroids described herein.
  • the methods of the invention include administering to the subject (e.g., a human) a combinatorial therapy including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable DMT agent (e.g., an immunomodulatory DMT agent), such as any of the DMT agents described herein, and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable symptom managing agent, such as any of the symptom managing agents described herein.
  • a combinatorial therapy including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable DMT agent (e.g., an immunomodulatory DMT agent), such as any of the DMT agents described herein, and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable symptom managing agent, such as any of the symptom managing agents described herein.
  • any suitable DMT agent e.g., an immunomodulatory DMT agent
  • any suitable symptom managing agent such as any of the
  • the methods of the invention include administering to the subject (e.g., a human) a combinatorial therapy including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable DMT agent (e.g., an immunomodulatory DMT agent), such as any of the DMT agents described herein, and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable corticosteroid, such as any of the corticosteroids described herein, and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable symptom managing agent, such as any of the symptom managing agents described herein.
  • any suitable DMT agent e.g., an immunomodulatory DMT agent
  • any suitable corticosteroid such as any of the corticosteroids described herein
  • any suitable symptom managing agent such as any of the symptom managing agents described herein.
  • the methods of the invention may include administering the corticosteroid and/or symptom managing agent either before or after administration of the DMT agent (e.g., an immunomodulatory DMT agent).
  • the corticosteroid and/or symptom managing agent is administered to the subject about 1 minute, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 40 hours, about 44 hours, or about 48 hours prior to administering the DMT agent (e.g., an immunomodulatory DMT agent).
  • the DMT agent e.g., an immunomodulatory DMT agent
  • the corticosteroid and/or symptom managing agent is administered to the subject about 1 minute, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 40 hours, about 44 hours, or about 48 hours after administering the DMT agent (e.g., an immunomodulatory DMT agent).
  • the DMT agent e.g., an immunomodulatory DMT agent
  • the methods of the invention may include administering the corticosteroid and/or symptom managing agent either before or after administration of the DMT agent (e.g., an immunomodulatory DMT agent).
  • the corticosteroid and/or symptom managing agent is administered to the subject 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 15 hours, 18 hours, 21 hours 24 hours, 27 hours, 30 hours, 33 hours, 36 hours, 40 hours, 44 hours, or 48 hours prior to administering the DMT agent (e.g., an immunomodulatory DMT agent).
  • the DMT agent e.g., an immunomodulatory DMT agent
  • the corticosteroid and/or symptom managing agent is administered to the subject 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 15 hours, 18 hours, 21 hours 24 hours, 27 hours, 30 hours, 33 hours, 36 hours, 40 hours, 44 hours, or 48 hours after administering the DMT agent (e.g., an immunomodulatory DMT agent).
  • the DMT agent e.g., an immunomodulatory DMT agent
  • Any suitable DMT agent e.g., immunomodulatory DMT agent, corticosteroid, and/or symptom managing agent described herein may be administered to a subject described herein (e.g., a subject with a C allele at polymorphism rs4962725 (SEQ ID NO: 1); a G allele at polymorphism rs3129882 (SEQ ID NO: 2); a G allele at polymorphism rs3091826 (SEQ ID NO: 3), a C allele at polymorphism rs3092737 (SEQ ID NO: 4); a C allele at polymorphism rs3092258 (SEQ ID NO: 5); an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6); and/or an equivalent allele that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), rs3129882 (SEQ ID NO: 2),
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Intrathecal administration is also contemplated.
  • the DMT agent e.g., an immunomodulatory DMT agent
  • corticosteroid e.g., corticosteroid, and/or symptom managing agent described herein may be administered to a subject described herein (e g., a subject with a C allele at polymorphism rs4962725 (SEQ ID NO: 1); a G allele at polymorphism rs3129882 (SEQ ID NO: 2); a G allele at polymorphism rs3091826 (SEQ ID NO: 3); and/or an equivalent allele at a polymorphism that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), rs3129882 (SEQ ID NO: 2), and/or rs3091826 (SEQ ID NO
  • the methods of the invention include administering to the subject having one or more of the genotypes described herein (e.g., a subject with a C allele at polymorphism rs4962725 (SEQ ID NO: 1); a G allele at polymorphism rs3129882 (SEQ ID NO: 2); a G allele at polymorphism rs3091826 (SEQ ID NO: 3); a T allele at orphism rs28672722 (SEQ ID NO: 9); a T allele at polymorphism rs37411 (SEQ ID NO: 10); a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); an A allele at polymorphism rs28359884 (SEQ ID NO: 12); and/or an equivalent allele at a polymorphism that is in linkage disequilibrium with rs4962725, rs312988
  • Immunomodulatory DMT agent(s) include one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more) of the following: an interferon beta (IFNP) agent; a monoclonal antibody (mAb); a sphingosine 1-phosphate receptor modulator; an anthracenedione antineoplastic; a pyrimidine synthesis inhibitor; a polymer of glutamic acid, lysine, alanine, and tyrosine; a fumarate agent; and an antimetabolite.
  • IFNP interferon beta
  • mAb monoclonal antibody
  • sphingosine 1-phosphate receptor modulator an anthracenedione antineoplastic
  • a pyrimidine synthesis inhibitor a polymer of glutamic acid, lysine, alanine, and tyrosine
  • fumarate agent and an antimetabolite.
  • the IFNP agent is selected from AVONEX® (interferon beta-la), BETASERON® (interferon beta-lb), EXTAVIA® (interferon beta-lb), PLEGRIDY® (peginterferon beta-la), and REBIF® (interferon beta- la). Any generic drug thereof is also envisioned.
  • the immunomodulatory DMT agent is a mAb.
  • the mAb is an anti-CD20 antibody (e.g., KESIMPTA® (ofatumumab).
  • the mAb is an anti-CD52 antibody (e.g., LEMTRADA® (alemtuzumab) or OCREVUS® (ocrelizumab)).
  • the mAb is an anti-a4pl integrin (very late antigen-4) antibody (e.g , TYSABRI® (natalizumab)).
  • the mAb is selected from KESIMPTA® (ofatumumab), LEMTRADA® (alemtuzumab), OCREVUS® (ocrelizumab), and TYSABRI® (natalizumab). Any generic drug thereof is also envisioned.
  • the immunomodulatory DMT agent is a sphingosine 1 -phosphate receptor modulator.
  • the sphingosine 1 -phosphate receptor modulator is selected from GlLENYA® (fingolimod), MAYZENT® (siponimod), PONVORYTM (ponesimod), and ZEPOSIA® (ozanimod). Any generic drug thereof is also envisioned.
  • the immunomodulatory DMT agent is an anthracenedione antineoplastic.
  • the anthracenedione antineoplastic is NOVANTRONE® (mitoxantrone). Any generic drug thereof is also envisioned.
  • the immunomodulatory DMT agent is a pyrimidine synthesis inhibitor.
  • the pyrimidine synthesis inhibitor is AUBAGIO® (teriflunomide). Any generic drug thereof is also envisioned.
  • the immunomodulatory DMT agent is a polymer of glutamic acid, lysine, alanine, and tyrosine.
  • the polymer of glutamic acid, lysine, alanine, and tyrosine is selected from COPAXONE® (glatiramer acetate), GLATOPA® (glatiramer acetate), and Glatiramer Acetate Injection (glatiramer acetate). Any generic drug thereof is also envisioned.
  • the immunomodulatory DMT agent is a fumarate agent.
  • the fumarate agent is selected from BAFIERTAMTM (monomethyl fumarate), Dimethyl Fumarate (dimethyl fumarate), TECFIDERA® (dimethyl fumarate), and VUMERITY® (diroximel fumarate).
  • the immunomodulatory DMT agent is an antimetabolite.
  • the antimetabolite is MAVENCLAD® (cladribine). Any generic drug thereof is also envisioned.
  • the present invention includes an immunomodulatory DMT agent for use in treating a subject suffering from MS, wherein the genotype of the subject has been determined to include a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6)).
  • each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6) indicates that the subject has an increased risk of MS progression.
  • the present invention includes an immunomodulatory DMT agent for use in treating a subject who has been previously diagnosed with MS and who has been previously determined to have one or more of a (i) G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882, thereby identifying the subject as having a risk of developing MS (e.g., an early onset of MS); (ii) G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)), thereby identifying
  • each G allele at polymorphism rs3129882 indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
  • each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)) indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
  • each T allele at polymorphism rs28672722 indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
  • the presence of each G allele at polymorphism rsl 1755689 indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
  • the presence of each A allele at polymorphism rs28359884 indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
  • the present invention includes an immunomodulatory DMT agent for use in preventing or reducing the likelihood of developing MS in a subject who has been previously determined to have one or more of a (i) G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (ii) G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); (iii) T allele at polymorphism rs28672722
  • each G allele at polymorphism rs3129882 indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
  • each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)) indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
  • each T allele at polymorphism rs28672722 indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
  • the presence of each G allele at polymorphism rsl 1755689 indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
  • the presence of each A allele at polymorphism rs28359884 indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
  • the present invention includes the use of an effective amount of an immunomodulatory DMT agent in the manufacture of a medicament for use in treating a subject suffering from MS, wherein the subject has been determined to include one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or seventeen of the following alleles: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1), (ii) an equivalent allele that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), (iii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), (iv) an equivalent allele that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2), (v) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), (vi) an equivalent
  • the present invention includes a composition including an effective amount of an immunomodulatory DMT agent for use in a method of treating a subject suffering from MS, wherein the subject has been determined to include one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or seventeen of the following alleles: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1), (ii) an equivalent allele that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), (iii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), (iv) an equivalent allele that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2), (v) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), (vi) an equivalent alleles: (i) a C
  • the methods of the invention include administering to the subject one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) additional therapeutic agents.
  • the one or more additional therapeutic agent is a corticosteroid.
  • the corticosteroid may be administered to the subject orally, intravenously, or by any other suitable administration route. Any suitable corticosteroid may be used (e.g., dexamethasone, methylprednisolone, prednisone, prednisolone, betamethasone, hydrocortisone, and the like).
  • the corticosteroid is selected from SOLU-MEDROL® (methylprednisolone) or DELTASONE® (prednisone). Any generic drug thereof is also envisioned.
  • the one or more additional therapeutic agents is a symptom managing agent for treatment of one or more symptoms of MS (e.g., a dysfunctional bladder, a bladder infection, a bowel dysfunction, depression, dizziness, vertigo, pseudobulbar affect, fatigue, itching, pain, a sexual problem, spasticity, tremors, and/or difficulty walking).
  • MS e.g., a dysfunctional bladder, a bladder infection, a bowel dysfunction, depression, dizziness, vertigo, pseudobulbar affect, fatigue, itching, pain, a sexual problem, spasticity, tremors, and/or difficulty walking.
  • the symptom managing agent is one that treats a subject’s dysfunctional bladder.
  • Any suitable symptom managing agent for a dysfunctional bladder may be used (e.g., onabotulinumtoxin A, desmopressin, tolterodine, oxybutynin, darifenacin, tamsulosin, mirabegron, oxybutynin, imipramine, solifenacin succinate, and any combination thereof).
  • the symptom managing agent for treating the subject’s dysfunctional bladder is selected from BOTOX® (onabotulinumtoxin A), DDAVP Nasal Spray (desmopressin), DETROL® (tolterodine), DTTROPAN® (oxybutynin), DTTROPAN XL®, ENABLEX® (darifenacin), FLOMAX® (tamsulosin), Prazosin, MYRBETRIQ® (mirabegron), OXYTROL® (oxybutynin), TOFRANIL® (imipramine), and VESICARE® (solifenacin succinate). Any generic drug thereof is also envisioned.
  • the symptom managing agent is one that treats a subject’s bladder infection.
  • Any suitable symptom managing agent for a bladder infection may be used (e.g., sulfamethoxazole, ciprofloxacin, levofloxacin, nitrofurantoin, methenamine, phenazopyridine, and any combination thereof).
  • the symptom managing agent for treating the subject’s bladder infection is selected from BACTRIM®, SEPTRA® (sulfamethoxazole), CIPO® (ciprofloxacin), LEVAQUIN® (levofloxacin), MACRODANTIM® (nitrofurantoin), HIPREX® (methenamine), and PYRIDIUM® (phenazopyridine). Any generic drug thereof is also envisioned.
  • the symptom managing agent is one that treats a subject’s bowel dysfunction.
  • Any suitable symptom managing agent for bowel dysfunction may be used (e.g., docusate, bisacodyl, docusate stool softener laxative, sodium phosphate, mineral oils, psyllium hydrophilic musilloid, magnesium hydroxide, glycerine, and any combination thereof).
  • the symptom managing agent for treating the subject’s bowel dysfunction is selected from COLACE® (docusate), DULCOLAX® (bisacodyl), ENEMEEZ® (docusate stool softener laxative), FLEET ENEMA® (sodium phosphate), a mineral oil, METAMUCIL® (psyllium hydrophilic musilloid), Phillips® Milk of Magnesia (magnesium hydroxide), and SANI-SUPP® suppository (glycerine). Any generic drug thereof is also envisioned.
  • the symptom managing agent is one that treats a subject’s depression.
  • the symptom managing agent for treating the subject’s depression is an antidepressant, such as a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), a norepinephrine dopamine reuptake inhibitor (NDRI), a serotonin partial agonist and reuptake inhibitor (SPARI), a serotonin antagonist and reuptake inhibitor (SARI), a monoamine oxidase inhibitor (MAOI), a N- methyl-d-aspartic acid (NMDA) antagonist, and noradrenergic and specific serotonergic antidepressant (NASSA).
  • SSRI selective serotonin reuptake inhibitor
  • SNRI serotonin norepinephrine reuptake inhibitor
  • TCA tricyclic antidepressant
  • NDRI
  • any suitable symptom managing agent for depression may be used (e.g., citalopram, duloxetine hydrochloride, venlafaxine, paroxetine, fluoxetine, fluoxetine, bupropion, sertraline, and any combination thereof).
  • the symptom managing agent for treating the subject’s depression e.g., an antidepressant
  • the symptom managing agent for treating the subject’s depression is selected from CELEXA® (citalopram), CYMBALTA® (duloxetine hydrochloride), EFFEXOR® (enlafaxine), PAXIL® (paroxetine), PROZAC® (fluoxetine), WELLBUTRIN® (bupropion), and ZOLOFT® (sertraline). Any generic drug thereof is also envisioned.
  • the symptom managing agent is one that treats a subject’s dizziness and/or vertigo.
  • Any suitable symptom managing agent for dizziness and/or vertigo may be used (e.g., meclizine).
  • the symptom managing agent for treating the subject’s dizziness and/or vertigo is ANTIVERT® (meclizine). Any generic drug thereof is also envisioned.
  • the symptom managing agent is one that treats a subject’s pseudobulbar affect.
  • Any suitable symptom managing agent for pseudobulbar affect may be used (e.g., dextromethorphan, quinidine, and any combination thereof).
  • the symptom managing agent for treating the subject’s pseudobulbar affect is is NUEDEXTA® (dextromethorphan and quinidine). Any generic drug thereof is also envisioned.
  • the symptom managing agent is one that treats a subject’s fatigue.
  • Any suitable symptom managing agent for fatigue may be used (e.g., dextroamphetamine, amphetamine, modafinil, modafinil, fluoxetine, methylphenidate, and any combination thereof).
  • the symptom managing agent for treating the subject’s fatigue is selected from ADDERALL® (dextroamphetamine and amphetamine), amantadine, PRO VIGIL® (modafinil), PROZAC® (fluoxetine), and RITALIN® (methylphenidate). Any generic drug thereof is also envisioned.
  • the symptom managing agent is one that treats a subject’s itchy skin. Any suitable symptom managing agent for itchiness may be used (e.g., hydroxyzine). In some embodiments, the symptom managing agent for treating a subject’s itchy skin is VISTARIL® (hydroxyzine). Any generic drug thereof is also envisioned. [000142] In some embodiments, the symptom managing agent is one that treats a subject’s pain.
  • Any suitable symptom managing agent for pain may be used (e.g., duloxetine, venlafaxine, amitriptyline, lamotrigine, pregabalin, gabapentin, nortriptyline HCL, nortriptyline, carbamazepine, oxcarbazepine, and any combination thereof).
  • a suitable symptom managing agent for pain e.g., duloxetine, venlafaxine, amitriptyline, lamotrigine, pregabalin, gabapentin, nortriptyline HCL, nortriptyline, carbamazepine, oxcarbazepine, and any combination thereof).
  • the symptom managing agent for treating the subject’s pain is selected from CYMBALTA® (duloxetine), EFFEXOR® (venlafaxine), ELAVIL® (amitriptyline), LAMICTAL® (lamotrigine), LYRICA® (pregabalin), NEURONTIN® (gabapentin), PAMELOR® (nortriptyline HCL), AVENTYL® (nortriptyline), TEGETRO® (carbamazepine), and TRILEPTAL® (oxcarbazepine). Any generic drug thereof is also envisioned.
  • the symptom managing agent is one that treats a subject’s sexual problem (e.g., sexual impotence and erectile dysfunction).
  • a subject e.g., sexual impotence and erectile dysfunction.
  • Any suitable symptom managing agent for a sexual problem may be used (e.g., tadalafil, vardenafd, alprostadil, avanafil, sildenafil, and any combination thereof).
  • the symptom managing agent for treating the subject’s sexual problem is selected from CIALIS® (tadalafil), LEVITRA® (vardenafd), MUSE® (alprostadil), PROSTIN VR® (alprostadil), STENDRA® (avanafil), and VIAGRA® (sildenafil). Any generic drug thereof is also envisioned.
  • the symptom managing agent is one that treats a subject’s spasticity.
  • Any suitable symptom managing agent for spasticity may be used (e.g., onabotulinumtoxin A, dantrolene, clonazepam, diazepam, tizanidine, and any combination thereof).
  • the symptom managing agent for treating the subject’s spasticity is selected from baclofen, BOTOX® (onabotulinumtoxin A), DANTRIUM® (dantrolene), KLONOPIN® (clonazepam), VALIUM® (diazepam), and ZANAFLEX® (tizanidine). Any generic drug thereof is also envisioned.
  • the symptom managing agent is one that treats a subject’s tremor.
  • Any suitable symptom managing agent for tremors may be used (e.g., isoniazid, clonazepam, and any combination thereof).
  • the symptom managing agent for treating the subject’s tremor is selected from LANIAZID® (isoniazid) and KLONOPIN® (clonazepam). Any generic drug thereof is also envisioned.
  • the symptom managing agent is one that treats a subject’s difficulty with walking.
  • Any suitable symptom managing agent for walking difficulty may be used (e.g., dalfampridine).
  • the symptom managing agent for treating the subject’s difficulty with walking is AMPYRA® (dalfampridine). Any generic drug thereof is also envisioned.
  • the methods of the invention include administering to the subject one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of the corticosteroids and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of the symptom managing agents described herein.
  • the present invention provides diagnostic methods of determining whether a subject is at risk of MS progression (e.g., in terms of rate of T2LVC, e.g., in a subject with CIS, RRMS, PPMS, or SPMS).
  • the present invention provides methods of selecting a therapy (e.g., a DMT agent (e.g., an immunomodulatory DMT agent)) for a subject based on the subject’s genotype at one or more genetic polymorphisms described herein (e.g., a polymorphism selected from rs4962725 (SEQ ID NO: 1), a polymorphism that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), rs3129882 (SEQ ID NO: 2), a polymorphism that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2), rs3091826 (SEQ ID NO: 3), a polymorphism that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3), rs28672722 (SEQ ID NO: 9), a polymorphism that is in linkage disequilibrium with rs28
  • the present invention further provides diagnostic methods of determining whether a subject is at risk of developing MS (e.g., an early onset of MS). Additionally, the present invention provides methods of selecting a therapy (e g., a DMT agent (e.g., an immunomodulatory DMT agent)) for a subject based on the subject’s genotype at one or more genetic polymorphisms described herein (e.g., a polymorphism selected from rs3129882 (SEQ ID NO: 2), rs3091826 (SEQ ID NO: 3), rs28672722 (SEQ ID NO: 9), rs37411 (SEQ ID NO: 10), and/or a polymorphism that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2) and/or rs3091826 (SEQ ID NO: 3) and/or rs28672722 (SEQ ID NO: 9) and/or rs37411 (S
  • the present invention further provides diagnostic methods of determining whether a subject is at risk of developing an early onset of MS (e.g., in terms of age-at-onset (AAO)). Additionally, the present invention provides methods of monitoring a subject determined to be at risk of developing an early onset of MS and selecting a therapy (e.g., a DMT agent (e.g., an immunomodulatory DMT agent)) for a subject based on the subject’s genotype at one or more genetic polymorphisms described herein (e.g., a polymorphism selected from rs3129882 (SEQ ID NO: 2); rs3091826 (SEQ ID NO: 3), rs28672722 (SEQ ID NO: 9), rs3741 1 (SEQ ID NO: 10), rsl 1755689 (SEQ ID NO: 11), rs28359884 (SEQ ID NO: 12), and/or a polymorphism that is in linkage disequilibrium with a DMT
  • the disclosure provides a method of selecting a therapy for a subject suffering from MS, the method including: (a) determining in a sample derived from a subject suffering from MS the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., polymorphism rsl0633091 (SEQ ID NO: 6)), wherein the presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rs!0633091 (SEQ ID NO: 6)) indicates that the subject has an increased risk of MS progression; and (b) selecting a therapy including a DMT (e.g., an immunomodulatory D
  • the subject’s genotype includes a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), such as polymorphism rs!0633091 (SEQ ID NO: 6).
  • the subject’s genotype includes an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6).
  • the disclosure provides a method of determining whether a subject is at increased risk of MS progression, the method including determining the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., polymorphism rsl0633091 (SEQ ID NO: 6)) in a sample derived from the subject, wherein the subject is at increased risk of MS progression if the genotype of the subject includes a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rs!0633091 (SEQ ID NO: 6)).
  • the subject’s genotype includes a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), such as polymorphism rsl0633091 (SEQ ID NO: 6).
  • subject’s genotype includes an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6).
  • the disclosure provides a method of selecting a therapy for a subject at risk of developing MS (e.g., an early onset of MS), the method including: (a) determining in a sample derived from a subject the genotype at one or more of (i) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium
  • the polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092737 (SEQ ID NO: 4).
  • the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4).
  • the polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092258 (SEQ ID NO: 5).
  • the equivalent allele is a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the disclosure provides a method of determining whether a subject is at increased risk of developing MS (e.g., and early onset of MS), the method including determining in a sample derived from the subject the genotype at one or more of (a) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the subject is at increased risk of developing MS (e.g., an early onset of MS) if the genotype of the subject includes a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with
  • the polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092737 (SEQ ID NO: 4).
  • the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4).
  • the polymorphism in linkage disequilibrium with polymorphism rs3091826 is polymorphism rs3092258 (SEQ ID NO: 5).
  • the equivalent allele is a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the disclosure provides a method of selecting a therapy for a subject at reduced risk of developing an early onset of MS, the method including: (a) determining in a sample derived from the subject the genotype at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each A allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a reduced risk of developing an early onset of MS; and (b) selecting a therapy including a DMT agent (e.g., an immunomodulatory DMT agent) for the subject who has been identified as having a risk of developing an early onset of MS.
  • a DMT agent e.g., an immunomodulatory D
  • the disclosure provides a method of determining whether a subject is at reduced risk of developing an early onset of MS, the method including determining the genotype at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) in a sample derived from the subject, wherein the subject is at reduced risk of developing an early onset of MS if the genotype of the subject includes an A allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2).
  • a therapy e.g., an immunomodulatory DMT agent
  • a therapy may be administered to the subject using the therapeutic methods described in Section II above.
  • the present disclosure provides for methods of treating a subject (e.g., a human) with one or more (e.g., 1, 2, 3, 4, 5, 6, or more) of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a C allele at polymorphism rs3092737 (SEQ ID NO: 4); (v) a C allele at polymorphism rs3092258 (SEQ ID NO: 5); (vi) an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6); (vii) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (viii)
  • a subject with a C allele at polymorphism rs4962725 (also referred to herein as “rs4962725C”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), e.g., an insertion of AG at polymorphism rs 10633091 (SEQ ID NO: 6), is at an increased risk of MS progression (e.g., in terms of rate of T2LVC), compared to a subject whose genotype does not contain a C allele (e.g., a subject containing a T allele) at polymorphism rs4962725 (SEQ ID NO: 1), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1).
  • a subject with a G allele at polymorphism rs3129882 (SEQ ID NO: 2) (also referred herein as “rs3129882G”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), is at risk of developing MS, such as an early age-at-onset (AAO) of MS, compared to a subject whose genotype does not contain a G allele (e.g., a subject containing an A allele) at polymorphism rs3129882 (SEQ ID NO: 2), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2).
  • AAO early age-at-onset
  • a subject with a G allele at polymorphism rs3091826 (SEQ ID NO: 3) (also referred herein as “rs3091826G”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5), is at risk of developing MS, such as an early AAO of MS, compared to a subject whose genotype does not contain a G allele (e.g., a subject containing an A or a T allele) at polymorphism rs3091826 (SEQ ID NO: 3), or the equivalent allele at the polymorphism in linkage disequilibrium with poly
  • a subject with a T allele at polymorphism rs28672722 (SEQ ID NO: 9), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9)
  • MS such as an early AAO of MS
  • the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9).
  • a subject with a T allele at polymorphism rs37411 (SEQ ID NO: 10), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) is at risk of developing MS, such as an early AAO of MS, compared to a subject whose genotype does not contain a T allele at polymorphism rs37411 (SEQ ID NO: 10), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10).
  • a subject with a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) is at risk of developing MS, such as an early AAO of MS, compared to a subject whose genotype does not contain a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11).
  • a subject with an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) is at risk of developing MS, such as an early AAO of MS, compared to a subject whose genotype does not contain an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
  • the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)).
  • the subject has the following genotype: a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882.
  • the subject has the following genotype: a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)).
  • a G allele at polymorphism rs3091826 SEQ ID NO: 3
  • an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the subject has the following genotype: a T allele at polymorphism rs28672722 (SEQ ID NO: 9), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9). In some embodiments, the subject has the following genotype: a T allele at polymorphism rs37411 (SEQ ID NO: 10), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10).
  • the subject has the following genotype: a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11).
  • the subject has the following genotype: an A allele at polymorphism rs28359884 (SEQ ID NO: 12), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
  • the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl 0633091 (SEQ ID NO: 6)); and a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882.
  • the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5))
  • the subject has the following genotype: a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882; and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)).
  • the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882; and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 1), and/or an equivalent
  • the subject has the genotype comprising or consisting of one or more of any of the following: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882; (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e)
  • the subject has any one of the following genotypes: a C allele at polymorphism rs4962725 (SEQ ID NO: 1); a G allele at polymorphism rs3129882 (SEQ ID NO: 2); a G allele at polymorphism rs3091826 (SEQ ID NO: 3); a T allele at polymorphism rs28672722 (SEQ ID NO: 9); a T allele at polymorphism rs37411 (SEQ ID NO: 10); a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); an A allele at polymorphism rs28359884 (SEQ ID NO: 12);an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO:
  • the subject has any two, three, four, five, six, seven, eight, nine, or ten of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in link
  • the subject has all of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725
  • the equivalent allele may be at an alternate single nucleotide polymorphism (SNP) that is in linkage disequilibrium with one or more of the selected SNPs described herein (e.g., rs4962725 (SEQ ID NO: 1); rs3129882 (SEQ ID NO: 2); rs3091826 (SEQ ID NO: 3)); rs28672722 (SEQ ID NO: 9); rs37411 (SEQ ID NO: 10); rsl 1755689 (SEQ ID NO: 11); and/or rs28359884 (SEQ ID NO: 12).
  • SNP alternate single nucleotide polymorphism
  • the equivalent allele that is in linkage disequilibrium with rs4962725 is an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6).
  • the equivalent allele that is in linkage disequilibrium with rs3091826 is a C allele at polymorphism rs3092737 (SEQ ID NO: 4).
  • the equivalent allele that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3) is a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the linkage disequilibrium is a D’ value or an r 2 value.
  • the D’ measure between the selected SNP and the alternate SNP is > 0.60 (e.g., > 0.60, > 0.65, > 0.7, > 0.75, > 0.8, > 0.85, > 0.9, > 0.95, or higher).
  • the D’ value between the selected SNP and the alternate SNP is >0.70, > 0.80, or > 0.90.
  • the D’ value between the selected SNP and the alternate SNP is 1.0.
  • the r 2 value between the selected SNP and the alternate SNP is > 0.60 (e.g., > 0.60, > 0.65, > 0.7, > 0.75, > 0.8, > 0.85, > 0.9, > 0.95, or higher). In some embodiments the r 2 value between the selected SNP and the alternate SNP is > 0.70, > 0.80, or > 0.90. In some embodiments, the r 2 value between the selected SNP and the alternate SNP is 1.0.
  • the equivalent allele may be the minor allele or the major allele. In some instances, the equivalent allele is the minor allele. In other instances, the equivalent allele is the major allele.
  • the genotype of the subject is derived from a sample of the subject, such as blood, plasma, serum, urine, saliva, stool, pleural fluid, lymphatic fluid, sputum, ascites, prostatic fluid, cerebrospinal fluid (CSF), or any other bodily secretion or derivative thereof.
  • the sample derived from the subject is a whole blood sample, a serum sample, a plasma sample, or a combination thereof.
  • the sample derived from the subject is a whole blood sample.
  • the sample derived from a subject is a serum sample.
  • the sample derived from a subject a plasma sample.
  • genotype of a subject can be determined using any of the methods or assays described herein or that are known in the art.
  • the methods of treatment (e.g., as described in Section II above) and/or diagnostic (e.g., as described in Section III above) provided by the invention involve determining of the genotype of a subject at one or more polymorphisms (e.g., SNPs) described herein (e.g., a subject with a C allele at polymorphism rs4962725 (SEQ ID NO: 1); a G allele at polymorphism rs3129882 (SEQ ID NO: 2); a G allele at polymorphism rs3091826 (SEQ ID NO: 3); a T allele at polymorphism rs28672722 (SEQ ID NO: 9); a T allele at polymorphism rs37411 (SEQ ID NO: 10); a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); an A allele at polymorphism rs283598
  • SNPs polymorphis
  • Determination of the presence or absence of a particular allele is generally performed by analyzing a nucleic acid sample that is obtained from the subject to be analyzed.
  • the nucleic acid sample includes genomic DNA.
  • the genomic DNA is typically obtained from blood samples but may also be obtained from other cells or tissues (e.g., hair or skin).
  • Detection techniques for evaluating nucleic acids for the presence of a SNP involve procedures well known in the field of molecular genetics. Many, but not all, of the methods involve amplification of nucleic acids. Ample guidance for performing amplification is provided in the art. Exemplary references include manuals such as Erlich, ed., PCR Technology: Principles and Applications for DNA Amplification, Freeman Press, 1992; Innis et al. eds., PCR Protocols: A Guide to Methods and Applications, Academic Press, 1990; Ausubel, ed., Current Protocols in Molecular Biology, 1994-1999, including supplemental updates through April 2004; and Sambrook et al.
  • Suitable amplification methods include ligase chain reaction (see, e.g., Wu et al. Genomics 4:560-569, 1988); strand displacement assay (see, e.g., Walker et al. Proc. Natl. Acad. Sci. USA 89:392-396, 1992; U.S. Pat. No. 5,455,166); and several transcription-based amplification systems, including the methods described in U.S. Pat. Nos. 5,437,990; 5,409,818; and 5,399,491; the transcription amplification system (TAS) (Kwoh et al. Proc. Natl.
  • TAS transcription amplification system
  • Detection of the genotype, haplotype, SNP, microsatellite, or other polymorphism of a subject can be performed using oligonucleotide primers and/or probes.
  • Oligonucleotides can be prepared by any suitable method, usually chemical synthesis. Oligonucleotides can be synthesized using commercially available reagents and instruments. Alternatively, they can be purchased through commercial sources. Methods of synthesizing oligonucleotides are well known in the art (see, e.g., Narang et al. Meth. Enzymol. 68:90-99, 1979; Brown et al. Meth. Enzymol.
  • modifications to the above-described methods of synthesis may be used to desirably impact enzyme behavior with respect to the synthesized oligonucleotides.
  • incorporation of modified phosphodiester linkages e.g., phosphorothioate, methylphosphonates, phosphoamidate, or boranophosphate
  • linkages other than a phosphoric acid derivative may be used to prevent cleavage at a selected site.
  • the use of 2’-amino modified sugars tends to favor displacement over digestion of the oligonucleotide when hybridized to a nucleic acid that is also the template for synthesis of a new nucleic acid strand.
  • genotype of a subject can be determined using many detection methods that are well known in the art. Most assays entail one of several well-known molecular techniques: hybridization using allele-specific oligonucleotides, primer extension, allele-specific ligation, sequencing, or electrophoretic separation techniques, e.g., single-stranded conformational polymorphism (SSCP) and heteroduplex analysis.
  • SSCP single-stranded conformational polymorphism
  • Exemplary assays include 5’-nuclease assays, template-directed dye-terminator incorporation, molecular beacon allele-specific oligonucleotide assays, single-base extension assays, and SNP scoring by real-time pyrophosphate sequences.
  • Analysis of amplified sequences can be performed using various technologies such as microchips, fluorescence polarization assays, and MALDI-TOF (matrix assisted laser desorption ionization-time of flight) mass spectrometry.
  • Two methods that can also be used are assays based on invasive cleavage with Flap nucleases and methodologies employing padlock probes.
  • RNA samples for the presence of polymorphic alleles.
  • mRNA can be used to determine the genotype of a subject at one or more polymorphic sites.
  • the nucleic acid sample is obtained from cells in which the target nucleic acid is expressed.
  • Such an analysis can be performed by first reverse-transcribing the target RNA using, for example, a viral reverse transcriptase, and then amplifying the resulting cDNA; or using a combined high-temperature reverse-transcription-polymerase chain reaction (RT- PCR), as described in U.S. Pat. Nos. 5,310,652; 5,322,770; 5,561,058, 5,641,864; and 5,693,517.
  • the invention provides a kit for carrying out the methods of the invention, for example, for determining the genotype of a subject at a polymorphism described herein. In some embodiments, the invention provides a kit for determining whether a subject is at risk of MS progression and/or at risk of developing an early onset of MS.
  • a kit of the invention may contain an oligonucleotide (e.g., a probe or primer) capable of specifically hybridizing to one of the following polymorphic alleles: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1), (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9), (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10), (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), (viii) an equivalent all
  • the kit contains an oligonucleotide capable of specifically hybridizing to a C allele at polymorphism rs4962725 (SEQ ID NO: 1). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a G allele at polymorphism rs3129882 (SEQ ID NO: 2). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a G allele at polymorphism rs3091826 (SEQ ID NO: 3). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a C allele at polymorphism rs3092737 (SEQ ID NO: 4).
  • the kit contains an oligonucleotide capable of specifically hybridizing to a C allele at polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an AG allele inserted at polymorphism rsl0633091 (SEQ ID NO: 6). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a T allele at polymorphism rs28672722 (SEQ ID NO: 9). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a T allele at polymorphism rs37411 (SEQ ID NO: 10).
  • the kit contains an oligonucleotide capable of specifically hybridizing to a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an A allele at polymorphism rs28359884 (SEQ ID NO: 12). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1).
  • the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs28672722 (SEQ ID NO: 9).
  • the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs37411 (SEQ ID NO: 10). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rsl 1755689 (SEQ ID NO: 11). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs28359884 (SEQ ID NO: 12).
  • Oligonucleotides “capable of specifically hybridizing” a genetic locus bind either to the polymorphic region of the locus or bind adjacent to the polymorphic region of the locus.
  • a genetic locus e.g., a genetic locus that includes a polymorphic allele or SNP
  • primers are adjacent if they are sufficiently close to be used to produce a polynucleotide including the polymorphic region.
  • oligonucleotides are adjacent if they bind within about 1-2 kb, e.g., less than 1 kb from the polymorphism. Specific oligonucleotides are capable of hybridizing to a sequence, and under suitable conditions will not bind to a sequence differing by a single nucleotide.
  • Oligonucleotides whether used as probes or primers, contained in a kit can be detectably labeled. Labels can be detected either directly, for example for fluorescent labels, or indirectly. Indirect detection can include any detection method known to one of skill in the art, including biotin-avidin interactions, antibody binding and the like. Fluorescently labeled oligonucleotides also can contain a quenching molecule. Oligonucleotides can be bound to a surface. In some embodiments, the surface is silica or glass. In some embodiments, the surface is a metal electrode.
  • the kit may contain one or more reagents (e.g., a buffer, preservative, and/or diluent) necessary to perform hybridization of the oligonucleotide to a subject’s nucleic acid sample.
  • the one or more reagents may be in the form of a liquid or a lyophilized powder and stored within one or more containers.
  • kits may further include a positive control, a negative control, sequencing markers, and/or sequencing primers. Kits may also include instructions for use and for interpreting the results obtained using the kit. V. Definitions
  • administering means the administration of a pharmaceutical composition (e.g., an immunomodulatory disease-modifying therapeutic (DMT) agent) to a subject (e.g., a subject suffering from multiple sclerosis (MS)).
  • a pharmaceutical composition e.g., an immunomodulatory disease-modifying therapeutic (DMT) agent
  • MS multiple sclerosis
  • compositions and methods are intended to mean that the compounds, compositions and methods include the recited elements, but not exclude others.
  • Consisting essentially of when used to define compounds, compositions and methods, shall mean excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants, e.g., from the isolation and purification method and pharmaceutically acceptable carriers, preservatives, and the like. “Consisting of’ shall mean excluding more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of this technology.
  • age-at-onsef refers to the age at which an individual acquires, develops, or first experiences symptoms of a disease or disorder (e.g., MS) or is diagnosed as having a disease or disorder (e.g., MS).
  • AAO for MS is about 20 to about 40 years of age.
  • Procedures for diagnosing MS may include one or more of the following: blood tests and/or spinal taps (lumbar puncture), e.g., to evaluate biomarkers associated with MS, magnetic resonance imaging (MRI), e.g., to evaluate lesions in the brain and/or spinal cord, evoked potential tests assessing electrical signals produced by the nervous system in response to stimuli (e.g., visual or electrical stimuli), and an oligoclonal band test for screening the cerebrospinal fluid (CSF) for immunoglobulin bands associated with MS.
  • blood tests and/or spinal taps e.g., to evaluate biomarkers associated with MS
  • MRI magnetic resonance imaging
  • evoked potential tests assessing electrical signals produced by the nervous system in response to stimuli (e.g., visual or electrical stimuli)
  • CSF cerebrospinal fluid
  • Alternate SNP when used herein refers to a SNP that is expected to behave similarly to a selected SNP and is selected based on similar allele frequencies and/or has linkage disequilibrium with a selected SNP as measured by an r 2 > 0.6 and/or D’ > 0.6.
  • Alternate SNPs include SNPs that are in linkage disequilibrium with the SNPs described herein (e.g., rs4962725 (SEQ ID NO: 1); rs3129882 (SEQ ID NO: 2); and rs3091826 (SEQ ID NO: 3)).
  • a subject suffering from refers to a subject showing clinical signs in respect to a certain disease, for example, any form of MS (e.g., clinically isolated syndrome (CIS), relapsingremitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS), progressive forms of MS (PMS), and relapsing MS (RMS)).
  • MS clinically isolated syndrome
  • RRMS relapsingremitting MS
  • PPMS primary progressive MS
  • SPMS secondary progressive MS
  • PMS progressive forms of MS
  • RMS relapsing MS
  • the term “early onset” refers to a disease, disorder, or condition occurring early in a subject’s life, e.g., in relation to other subjects with the disease, disorder, or condition.
  • subjects with a G allele at polymorphism rs3129882 (SEQ ID NO: 2) are more likely to experience an early onset of MS compared to subjects with an A allele at polymorphism rs3129882.
  • the presence of one copy of an A allele at polymorphism rs3129882 delays AAO by approximately 1.24 years.
  • subjects with a G allele at polymorphism rs3091826 are more likely to experience an early onset of MS compared to subjects with an A or a T allele at polymorphism rs3091826.
  • the presence of one copy of a G allele reduces the AAO by about 3 years.
  • subjects with a C allele at polymorphism rs3092737 (SEQ ID NO: 4) or a C allele at polymorphism rs3092258 (SEQ ID NO: 5) are also more likely to experience an early onset of MS.
  • subjects with a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or a T allele at polymorphism rs37411 (SEQ ID NO: 10) were more likely to experience an early onset of MS.
  • subjects with a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an A allele at polymorphism rs28359884 (SEQ ID NO: 12) were more likely to experience an early onset of MS.
  • “Equivalent allele” or “surrogate allele,” as used herein, refers to an allele that is expected to behave similarly to a risk allele and is selected based on allele frequencies and/or high r 2 value (greater than or equal to (>) 0.6) and/or high D’ value (>0.6) with the risk alleles and/or selected SNP as defined herein.
  • the high r 2 value is > 0.6, > 0.7, >0.8, >0.9, or 1.0.
  • the high D’ value is > 0.6, > 0.7, > 0.8, > 0.9, or 1.0.
  • the term “effective amount” refers to an amount of a drug effective to treat a disease or disorder (e.g., MS (e.g., CIS, RRMS, PPMS, SPMS, PMS, and RMS)) in a subject or subject, such as a mammal, e.g., a human.
  • a disease or disorder e.g., MS (e.g., CIS, RRMS, PPMS, SPMS, PMS, and RMS)
  • a subject or subject such as a mammal, e.g., a human.
  • genotype refers to a description of the alleles of a gene contained in a subject or a sample. In the context of this invention, no distinction is made between the genotype of a subject and the genotype of a sample originating from the subject. Although typically a genotype is determined from samples of diploid cells, a genotype can be determined from a sample of haploid cells, such as a sperm cell.
  • the terms “disease modifying therapeutic agent” and “DMT agent” refer to a therapeutic agent that prevents or mitigates the severity of relapse events, the frequency of relapse events, the accumulation of disability, and the accumulation of new lesions in the brain and/or spinal cord in a subject with MS.
  • the DMT agent may be an “immunomodulatory DMT agent,” which may confer therapeutic benefit by modulating or suppressing the immune system.
  • immunomodulatory DMT agents include: interferon beta (IFNP) agents; monoclonal antibodies (mAbs); sphingosine 1-phosphate receptor modulators; anthracenedione antineoplastics; pyrimidine synthesis inhibitors; polymers of glutamic acid, lysine, alanine, and tyrosine; fumarate agents; and antimetabolites.
  • IFNP interferon beta
  • mAbs monoclonal antibodies
  • sphingosine 1-phosphate receptor modulators anthracenedione antineoplastics
  • pyrimidine synthesis inhibitors polymers of glutamic acid, lysine, alanine, and tyrosine
  • fumarate agents and antimetabolites.
  • a “kit” is any manufacture (e.g., a package or container) that includes at least one reagent, for example, a probe for determining the genotype of a polymorphism as described herein.
  • the manufacture may be promoted, distributed, or sold as a unit for performing the methods of the present invention.
  • Linkage disequilibrium refers to alleles at different loci that are not associated at random, i.e., not associated in proportion to their frequencies. If the alleles are in positive linkage disequilibrium, then the alleles occur together more often than expected assuming statistical independence. Conversely, if the alleles are in negative linkage disequilibrium, then the alleles occur together less often than expected assuming statistical independence.
  • MS progression refers to a progression or accumulation of T2 hyperintense lesion volume (T2LV) in a subject with MS.
  • MS progression can be observed by standard MRI techniques (e.g., observing an accumulation of lesions in the brain, as observed by MR1, over at least two time points). See the definition of “T2 magnetic resonance imaging lesion volume change” and “T2LVC” for additional context.
  • composition refers to a sterile preparation that is in such form as to permit the biological activity of the medicament to be effective, and which contains no additional components that are unacceptably toxic to a subject to which the formulation would be administered
  • a nucleotide position in a genome at which more than one sequence is possible in a population is referred to herein as a “polymorphism” or “polymorphic site.”
  • a polymorphic site may be a nucleotide sequence of two or more nucleotides, an inserted nucleotide or nucleotide sequence, a deleted nucleotide or nucleotide sequence, or a microsatellite, for example.
  • a polymorphic site that is two or more nucleotides in length may be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more, 20 or more, 30 or more, 50 or more, 75 or more, 100 or more, 500 or more, or about 1000 nucleotides in length, where all or some of the nucleotide sequences differ within the region.
  • a polymorphic site which is a single nucleotide in length is referred to herein as a single nucleotide polymorphism (SNP), as described below.
  • SNP single nucleotide polymorphism
  • each nucleotide sequence is referred to as a “polymorphic variant” or “nucleic acid variant.”
  • Each possible variant in the DNA sequence is referred to as an “allele.”
  • the first identified allelic form is arbitrarily designated as the reference form and other allelic forms are designated as alternative or variant alleles.
  • a “common” allele is an allele that is prevalent in a given population, e.g., the allele is present in multiple members of a population at a generally accepted frequency of greater than about 2%.
  • the polymorphic variant represented in a majority of samples from a population is referred to as a “prevalent allele,” or “major allele,” and the polymorphic variant that is less prevalent in the population is referred to as an “uncommon allele” or “minor allele.”
  • a subject who carries two prevalent alleles or two uncommon alleles is “homozygous” with respect to the polymorphism.
  • a subject who carries one prevalent allele and one uncommon allele is “heterozygous” with respect to the polymorphism.
  • C/G or A/T SNPs the alleles are ambiguous and dependent on the strand used to extract the data from the genotyping platform. With these C/G or A/T SNPs, the C or G nucleotide or the A or T nucleotide, respectively, may be the risk allele and is determined by correlation of allele frequencies.
  • the allele that correlates with an increased risk for a disease or disorder e.g., MS
  • increased risk for progression for a disease or disorder e.g., MS
  • T2LVC rate of T2 magnetic resonance imaging lesion volume change
  • age at onset for a disease or disorder e.g., MS
  • an odds ratio or relative risk of >1 may be referred to as the “risk allele” or “effect allele.”
  • the “risk allele” or “effect allele” may be the minor allele or major allele
  • sample and “biological sample” are used interchangeably to refer to any biological sample obtained from a subject including body fluids, body tissue, nasal samples (including nasal swabs or nasal polyps), sputum, cells, or other sources.
  • Body fluids include, e.g., lymph, sera, whole fresh blood, frozen whole blood, plasma (including fresh or frozen), peripheral blood mononuclear cells, urine, saliva, semen, synovial fluid and spinal fluid. Methods for obtaining tissue biopsies and body fluids from mammals are well known in the art.
  • single nucleotide polymorphism refers to a single base substitution within a DNA sequence that leads to genetic variability. Single nucleotide polymorphisms may occur at any region of a gene. In some instances, the polymorphism can result in a change in protein sequence. The change in protein sequence may affect protein function or not.
  • selected SNP refers to a SNP selected from the group consisting of polymorphism rs4962725 (SEQ ID NO: 1); rs3129882 (SEQ ID NO: 2); and rs3091826 (SEQ ID NO: 3).
  • subject refers to any single animal, more specifically a mammal (including such non-human animals as, for example, dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates) for which diagnosis or treatment is desired. Even more specifically, the subject herein is a human that is diagnosed with any form of MS (e.g., CIS, RRMS, PPMS, SPMS, PMS, and RMS).
  • MS e.g., CIS, RRMS, PPMS, SPMS, PMS, and RMS.
  • T2 magnetic resonance imaging lesion volume (T2LV) change” and “T2LVC” refer to a progression or accumulation of T2LV in a subject with MS that can be used as a measure of MS progression.
  • T2LVC can be assessed by imaging lesions (e.g., T2LV) in the brain, as observed by MRI, over at least two or more time points.
  • T2LVC may be computed as the percent change in T2LV from the first to the last brain MRI.
  • “therapy” or “treatment” refers to clinical intervention in an attempt to alter the natural course of the subject or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of a relapse of MS, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • Example 1 Genome-wide study for T2 MRI lesion volume progression rate in multiple sclerosis identifies a novel association in CTBP2
  • MS PATHS Partners Advancing Technology and Health Solutions
  • WGS Whole-genome sequencing
  • the rs3091826G allele in ETA? was associated with an increased risk of developing an early AAO for MS; subjects with one copy of the rs3091826G allele experienced onset of MS about 3 year earlier than subjects with the rs3091826A or rs3091826T allele.
  • Two equivalent alleles (i.e., surrogate alleles) in linkage disequilibrium with polymorphism rs3091826G were also identified: a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
  • the EYA2 locus harbors known associations with waist-to-hip ratio (rsl 1698093).
  • the rs3129882A allele in HLA-DRA was associated with a decreased risk of developing an early AAO for MS; subjects with one copy of the rs3129882A allele experienced onset of MS about 1.24 years later than subjects with the rs3129882G allele.
  • CTBP2 locus harbors known super-enhancers for oligodendrocytes and astrocytes, and known associations with brain cortical thickness and surface area (rs 1915146).
  • rslO633O91CAG polymorphism rsl0633091
  • the rsl0633091CAG allele is an insertion of AG nucleotides following the C nucleotide located at chromosome (chr) 10, nucleotide position 125044448 (i.e., chrlO: 125044448), e.g., relative to Genome Reference Consortium Human Build 38 patch release 13 (GRCh38.pl3).
  • Example 2 Adaptive and innate immunity are key drivers of age at onset of multiple sclerosis
  • MS age at onset is an objective and influential predictor of the evolution of MS independent of disease duration; earlier AAO is associated with greater frequency of relapse during the relapsing-remitting (RR) stage of MS, whereas a later AAO is associated with reaching disability milestones and transitioning to the secondary progressive (SP) stage sooner than individuals with earlier-onset MS.
  • RR relapsing-remitting
  • SP secondary progressive
  • Females tend to have an earlier AAO, and there is a strong genetic correlation within families.
  • MS risk variant HLA-DRB 1*15:01 has been shown to confer earlier AAO, and an increasing load of MS genetic risk variants have also been associated with an earlier AAO.
  • Few genome-wide association (GW A) analyses have been conducted to investigate direct genetic associations with MS AAO.
  • Existing studies have largely been limited to candidate studies and modestly-powered association analyses, showing little genetic association with MS outside of the major histocompatibility complex (MHC).
  • MHC major
  • the present study provides updated insights into the mechanisms driving early presentation of MS using a well-powered genome-wide association study (GWAS) of AAO in 3,905 persons with MS (PwMS).
  • GWAS genome-wide association study
  • Genome-wide association analyses were conducted in each trial for AAO (rank- normalized) using linear additive models adjusting for age at enrollment, sex, and ten principal components. Fixed-effects meta-analysis was used to meta-analyze the resulting summary statistics across the six cohorts. Gene-based tests of association were performed using MAGMA vl.06 (de Leeuw et al., PLoS Comput. Biol., //(4):e l 004219 (2015)) in FUMA. Pathway enrichment was evaluated in gene-level associations of p ⁇ 0.01 using Enrichr (Kuleshov et al., Nucleic Acids Res.
  • GS1 The first gene set (GS1) consisted of unique genes in which genic SNPs (as defined by MAGMA) had an AAO association p-value ⁇ 0.0001; genic SNPs were defined using exact gene boundaries (no flanking regions). SNP annotation was performed using SeattleSeq.
  • the union of GS1 and GS2 comprised the third gene set (GS3).
  • Pathway enrichment analysis was performed in Enrichr, utilizing the Reactome 2022 database, the KEGG 2021 Human database, and the Human Molecular Signatures Database Hallmark 2020 collection to characterize pathways and diseases enriched in gene sets one through three.
  • Enrichr creates an odds ratio for each enriched pathway from the z-score of the standard deviation of the expected rank, as calculated by a Fisher Exact Test for many random gene sets in the gene-set library. A corresponding p-value is produced from the Fisher Exact Test and taken the natural logarithm of, which is then multiplied by the z-score to calculate the “Combined Score”.
  • MS AAO major histocompatibility complex
  • r2 ⁇ 0.30 three independent signals that were not in LD with HLA-DRB1*15:O1 (r2 ⁇ 0.08).
  • HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPB1, BRD2, N0TCH4, PRRT1, and C4A were in perfect LD with expression quantitative trait loci (eQTLs) for several HLA and non-HLA genes across multiple tissues, including HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPB1, BRD2, N0TCH4, PRRT1, and C4A, and others (p ⁇ 5.0*10‘ 8 ).
  • non-MHC loci with suggestive independent associations include an intergenic variant on chromosome 7p 15.3, rs6461685T, that is associated with the expression of adjacent genes: KLHL7, KLPIL7-DT, NUPL2, and GPNMB, and rsl44445292A, and intronic HHIPL1 variant on 14q32.2.
  • KLHL7 has been associated with risk of Parkinson’s Disease.
  • REACTOME Interferon Gamma Signaling
  • MSigDB Interferon Gamma Response
  • Odds ratio the ratio describing the proportion of genes assigned to a given pathway as compared to the number expected by chance alone.

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Abstract

The present invention is directed to methods of treating subjects suffering from multiple sclerosis (MS). The methods of the invention include administering a therapy (e.g., an immunomodulatory disease-modifying therapeutic (DMT) agent) to a subject based on the presence of at least one genetic polymorphism described herein. The polymorphisms described herein were found to be associated with risk of developing MS, such as an early onset of MS, and an increased risk of MS progression.

Description

THERAPEUTIC AND DIAGNOSTIC METHODS FOR MULTIPLE SCLEROSIS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63/388,439, filed July 12, 2022, and U.S. Provisional Patent Application No. 63/446,741, filed February 17, 2023, the entire contents of each of which is incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention is directed to methods of monitoring and/or treating subjects suffering from multiple sclerosis (MS), methods of selecting a therapy for a subject suffering from MS or at risk of developing an early onset of MS, and methods of determining whether a subject is at increased risk of MS progression or at risk of developing an early onset of MS.
BACKGROUND
[0003] Multiple sclerosis (MS) is more common than previously thought and affects approximately 900,000 Americans. Approximately 10% of MS subjects have primary progressive multiple sclerosis (PPMS), a form of MS characterized by steady accumulation of disability without attacks typically seen in relapsing MS (RMS). In the modern treatment era, approximately 24% of subjects with RMS transition to secondary progressive MS (SPMS), characterized by insidious worsening of disability without further relapses, within 20 years from disease onset. Subjects with progressive forms of MS (PMS) are characterized by gradual accrual of disability over time, independent of relapses, resembling that of neurodegenerative disorders. Studies have identified over 200 loci, which are largely autoimmune loci, associated with MS risk, validating the immunomodulatory mechanisms of MS therapies. While therapies are effective for suppressing MS disease activity, they are only modestly effective in preventing disability progression.
[0004] Therefore, improved therapeutic and diagnostic methods for MS are needed.
SUMMARY OF THE INVENTION
[0005] The present invention is directed, inter alia, to methods of monitoring and/or treating subjects suffering from MS, methods of selecting a therapy for a subject suffering from MS or at risk of developing an early onset of MS, and methods of determining whether a subject is at increased risk of MS progression and/or at risk of developing an early onset of MS. [0006] In a first aspect, the disclosure encompasses a method of treating a subject suffering from MS, the method comprising administering to the subject a therapy comprising an immunomodulatory disease-modifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of: (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (d) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (e) a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (f) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (g) an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[0007] In one aspect, the invention features a method of determining whether a subject is at increased risk of MS progression, the method comprising determining in a sample derived from a subject suffering from MS the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of a C allele at polymorphism rs4962725 (SEQ ID NO: 1), or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), indicates that the subject has an increased risk of MS progression.
[0008] In some aspects, the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), compared to a subject whose genotype does not comprise a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1). [0009] In another aspect, the disclosure encompasses a method of treating a subject suffering from multiple sclerosis (MS), the method comprising: (a) determining in a sample derived from a subject suffering from MS the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression, and/or (b) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject who has been identified as having an increased risk of MS progression.
[00010] In some aspects, the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) is polymorphism rslO633O91 (SEQ ID NO: 6), and the equivalent allele is an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6).
[00011] In some aspects, the risk of MS progression is in terms of rate of T2 magnetic resonance imaging lesion volume change (T2LVC).
[00012] In some aspects, the method further comprises administering an immunomodulatory disease-modifying therapeutic agent to the subject.
[00013] In one aspect, the invention features a method of determining whether a subject is at risk of developing an early onset of MS, the method comprising determining in a sample derived from the subject the genotype at one or more of: (a) polymorphism rs3129882 (SEQ ID NO: 2), wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) polymorphism rs309I826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) in a sample derived from the subject, wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) polymorphism rs28672722 (SEQ ID NO: 9) in a sample derived from the subject, wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (d) polymorphism rs37411 (SEQ ID NO: 10) in a sample derived from the subject, wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs37411 (SEQ ID NO: 10), or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (e) polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (f) polymorphism rs28359884 (SEQ ID NO: 12) wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[00014] In some aspects, the subject is at risk of developing an early onset of MS if the genotype of the subject comprises one or more of (a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) a T allele at polymorphism rs28672722 (SEQ ID NO: 9), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), compared to a subject whose genotype does not comprise a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (d) a T allele at polymorphism rs37411 (SEQ ID NO: 10), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), compared to a subject whose genotype does not comprise a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (e) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), compared to a subject whose genotype does not comprise a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (f) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), compared to a subject whose genotype does not comprise an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[00015] In some aspects, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092737 (SEQ ID NO: 4) and/or polymorphism rs3092258 (SEQ ID NO: 5), and the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
[00016] In some aspects, the method further comprises (a) monitoring the subject who has been identified as having a risk of developing an early onset of MS for one or more symptoms of MS; (b) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and (c) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject diagnosed with MS.
[00017] In another aspect, the invention features a method of treating a subject having an increased risk of MS progression, the method comprising administering to the subject a therapy comprising an immunomodulatory disease-modifying therapeutic agent, wherein the genotype of the subject has been determined to comprise a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), indicating that the subject is at increased risk for MS progression.
[00018] In one aspect, the invention features a method of treating a subject having an increased risk of early onset of MS, the method comprising administering to the subject a therapy comprising an immunomodulatory disease-modifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of: (a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), indicating that the subject is at increased risk for early onset of MS; (b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), indicating that the subject is at increased risk for early onset of MS; (c) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), indicating that the subject is at increased risk for early onset of MS; (d) a T allele at polymorphism rs37411 (SEQ ID NO: 10), or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), indicating that the subject is at increased risk for early onset of MS; (e) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), indicating that the subject is at increased risk for early onset of MS; and/or (f) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), indicating that the subject is at increased risk for early onset of MS.
[00019] Tn another aspect, the disclosure encompasses a method of treating a subject having an increased risk of early onset of MS and/or an increased risk of MS progression, the method comprising administering to the subject a therapy comprising an immunomodulatory diseasemodifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of: (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: I), indicating that the subject is at increased risk for MS progression; (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), indicating that the subject is at increased risk for early onset of MS; (c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), indicating that the subject is at increased risk for early onset of MS; (d) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), indicating that the subject is at increased risk for early onset of MS; (e) a T allele at polymorphism rs37411 (SEQ ID NO: 10), or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), indicating that the subject is at increased risk for early onset of MS; (f) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), indicating that the subject is at increased risk for early onset of MS; and/or (g) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), indicating that the subject is at increased risk for early onset of MS.
[00020] In another aspect, the invention features a method of preventing or reducing the likelihood of developing MS in a subject, the method comprising administering to the subject a therapy comprising an immunomodulatory disease-modifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of: (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (d) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (e) a T allele at polymorphism rs37411 (SEQ ID NO: 10), or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (f) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (g) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[00021] In another aspect, the disclosure encompasses a method of preventing and/or reducing the likelihood of developing MS in a subject, the method comprising: (a) determining in a sample derived from the subject the genotype at one or more of: (i) polymorphism rs3129882 (SEQ ID NO: 2), or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS; (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of early onset of MS; (iii) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk of early onset of MS; (iv) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of early onset of MS; (v) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of early onset of MS; and/or (vi) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of early onset of MS; and (b) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject who has been identified as having a risk of developing an early onset of MS;.
[00022] In another aspect, the invention features a method of selecting a therapy for preventing and/or reducing the likelihood of developing MS in a subject, the method comprising: (a) determining in a sample derived from a subject the genotype at one or more of: (i) polymorphism rs3129882 (SEQ ID NO: 2), or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS;; (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of early onset of MS; (iii) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk of early onset of MS; (iv) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of early onset of MS; (v) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of early onset of MS; and/or (vi) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of early onset of MS; and (b) selecting a therapy comprising an immunomodulatory disease-modifying therapeutic agent for the subject who has been identified as having a risk of developing an early onset of MS.
[00023] In another aspect, the subject is at risk of developing an early onset of MS if the genotype of the subject comprises one or more of: (a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (c) a T allele at polymorphism rs28672722 (SEQ ID NO: 9), compared to a subject whose genotype does not comprise a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (d) a T allele at polymorphism rs37411 (SEQ ID NO: 10), compared to a subject whose genotype does not comprise a T allele at polymorphism rs37411 (SEQ ID NO: 10); (e) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), compared to a subject whose genotype does not comprise a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (!) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), compared to a subject whose genotype does not comprise an Aallele at polymorphism rs28359884 (SEQ ID NO: 12).
[00024] In another aspect, the invention features a method of monitoring and/or treating a subject having a risk of developing an early onset of MS, the method comprising: (a) determining in a sample derived from a subject if the genotype of the subject comprises one or more of: (i) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS; (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has a risk of developing an early onset of MS; (iii) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has a risk of developing an early onset of MS; (iv) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has a risk of developing an early onset of MS; (v) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has a risk of developing an early onset of MS; and/or (vi) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has a risk of developing an early onset of MS; (b) monitoring the subject identified as having a risk of developing an early onset of MS for one or more symptoms of MS; (c) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and (d) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject diagnosed with MS.
[00025] In another aspect, the invention features a method of treating a subject who has been previously determined to comprise one or more of (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10), or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), thereby identifying the subject as having a risk of developing an early onset of MS, and who has been previously diagnosed with MS, the method comprising administering to the subject a therapy comprising an immunomodulatory diseasemodifying therapeutic agent.
[00026] In some aspects, the invention features a method further comprising: (a) monitoring the subject who has been identified as having a risk of developing an early onset of MS for one or more symptoms of MS; (b) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and (c) administering a therapy comprising an immunomodulatory diseasemodifying therapeutic agent to the subject diagnosed with MS.
[00027] In another aspect, the invention features a method of selecting a therapy for a subject at risk of developing an early onset of MS, the method comprising: (a) determining in a sample derived from a subject the genotype at one or more of: (i) polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), indicates that the subject has a risk of developing an early onset of MS; (ii) polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), indicates that the subject has a risk of developing an early onset of MS; (iii) polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), indicates that the subject has a risk of developing an early onset of MS; (iv) polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), indicates that the subject has a risk of developing an early onset of MS; (v) polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), indicates that the subject has a risk of developing an early onset of MS; and/or (vi) polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), indicates that the subject has a risk of developing an early onset of MS; and (b) selecting a therapy comprising an immunomodulatory disease-modifying therapeutic agent for the subject who has been identified as having a risk of developing an early onset of MS. In some aspects, the invention features a method further comprising: (a) monitoring the subject who has been identified as having a risk of developing an early onset of MS for one or more symptoms of MS; (b) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and (c) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject diagnosed with MS.
[00028] In another aspect, the disclosure encompasses a method of selecting a therapy for a subject suffering from MS, the method comprising: (a) determining in a sample derived from a subject suffering from MS the genotype at one or more of: (i) polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression; and/or (ii) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of early onset of MS; (iii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of early onset of MS; (iv) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk of early onset of MS; (v) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of early onset of MS; (vi) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of early onset of MS; and/or (vii) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of early onset of MS; and (b) selecting a therapy comprising an immunomodulatory disease-modifying therapeutic agent for the subject who has been identified as having an increased risk of MS progression and/or early onset of MS.
[00029] In another aspect, the invention features an immunomodulatory disease-modifying therapeutic agent for use in a method of monitoring and treating a subject having a risk of developing an early onset of MS, the method comprising: (a) determining in a sample derived from a subject the genotype at one or more of: (i) polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS; and/or (ii) polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has a risk of developing an early onset of MS; (iii) polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has a risk of developing an early onset of MS; (iv) polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has a risk of developing an early onset of MS; (v) polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has a risk of developing an early onset of MS; and (vi) polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has a risk of developing an early onset of MS; (b) monitoring the subject identified as having a risk of developing an early onset of MS for one or more symptoms of MS; (c) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and (d) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject diagnosed with MS.
[00030] In another aspect, described is an immunomodulatory disease-modifying therapeutic agent for use in treating a subject suffering from MS, wherein the genotype of the subject has been determined to comprise one or more of: (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (d) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (e) a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (f) a G allele at polymorphism rsl 1755689 (SEQ ID NO:
11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (g) an A allele at polymorphism rs28359884 (SEQ ID NO:
12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12). In a further aspect, (a) the presence of a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression; (b) the presence of a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of developing an early onset of MS; (c) the presence of a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of developing an early onset of MS; (d) the presence of a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk an early onset of MS; (e) the presence of a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk an early onset of MS; (f) the presence of a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk an early onset of MS; and/or (g) the presence of an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk an early onset of MS. [00031] In another aspect, described is an immunomodulatory disease-modifying therapeutic agent for use in a method of treating a subject suffering from MS, the method comprising: (a) determining in a sample derived from a subject suffering from MS the genotype at: (i) polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression; (ii) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of developing an early onset of MS; (iii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of an early onset of MS; (iv) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk an early onset of MS; (v) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of an early onset of MS; (vi) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of an early onset of MS; and/or (vii) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of an early onset of MS; and (b) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject who has been identified as having an increased risk of MS progression and/or an increased risk of early onset of MS.
[00032] In another aspect, described is an immunomodulatory disease-modifying therapeutic agent for use in treating a subject who has who has been previously diagnosed with MS and who has been previously determined to comprise one or more of: (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), thereby indicating that the subject has an increased risk of MS progression; (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), thereby identifying the subject as having a risk of developing an early onset of MS; (c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs309I826 (SEQ ID NO: 3), thereby identifying the subject as having a risk of developing an early onset of MS; (d) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), thereby indicating that the subject has an increased risk of MS progression; (e) a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), thereby indicating that the subject has an increased risk of MS progression; (f) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), thereby indicating that the subject has an increased risk of MS progression; and/or (g) an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), thereby indicating that the subject has an increased risk of MS progression.
[00033] In one aspect, described is an immunomodulatory disease-modifying therapeutic agent for use in preventing and/or reducing the likelihood of developing MS in a subject who has been previously determined to comprise one or more of: (a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), thereby identifying the subject as having a risk of developing an early onset of MS; and/or (b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), thereby identifying the subject as having a risk of developing an early onset of MS; and/or (c) a T allele at polymorphism rs28672722 (SEQ ID NO: 9), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), thereby identifying the subject as having a risk of developing an early onset of MS; (d) a T allele at polymorphism rs37411 (SEQ ID NO: 10), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), thereby identifying the subject as having a risk of developing an early onset of MS; (e) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), thereby identifying the subject as having a risk of developing an early onset of MS; and/or (f) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), thereby identifying the subject as having a risk of developing an early onset of MS.
[00034] Also described is a kit for determining whether a subject is at increased risk of MS progression, the kit comprising one or more reagents for determining the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) in a sample derived from a subject, and instructions for use, wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1).
[00035] In another aspect, described is a kit for determining whether a subject is at a risk of developing an early onset of MS, the kit comprising one or more reagents for determining the genotype at one or more of: (a) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at the polymorphism in linkage disequilibrium with rs28672722 (SEQ ID NO: 9); (d) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (e) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (f) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[00036] Also described is a kit for determining whether a subject is at increased risk of MS progression and/or whether a subject is at a risk of developing an early onset of MS, the kit comprising one or more reagents for determining the genotype at one or more of: (a) polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) in a sample derived from a subject, and instructions for use, wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (b) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (c) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (d) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at the polymorphism in linkage disequilibrium with rs28672722 (SEQ ID NO: 9); (e) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (f) polymorphism rsl 1755689 (SEQ ID NO: l l) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (g) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12). [00037] In another aspect, the invention features a kit for determining whether a subject is at increased risk of MS progression, the kit comprising and instructions for use and one or more reagents for determining the genotype in a sample derived from a subject, (a) at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); and/or (b) at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); and/or (c) at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); and/or (d) at polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (e) at polymorphism rs37411 (SEQ ID NO: 10), or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a T allele at polymorphism rs37411 (SEQ ID NO: 10), or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (f) at polymorphism rsl 1755689 (SEQ ID NO: 11), or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (g) at polymorphism rs28359884 (SEQ ID NO: 12), or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the subject is at increased risk of MS progression if the genotype of the subject comprises an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[00038] In some aspects, the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) is polymorphism rslO633O91 (SEQ ID NO: 6), and the equivalent allele is an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6).
[00039] In some aspects, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092737 (SEQ ID NO: 4) and/or polymorphism rs3092258 (SEQ ID NO: 5), and the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
[00040] In some aspects, the methods of the invention further comprise administering an immunomodulatory disease-modifying therapeutic agent to the subject.
[00041] In some aspects of the methods of the invention, the subject’s genotype is determined from a sample derived from the subject selected from a whole blood sample, a serum sample, a plasma sample, or a combination thereof. In some aspects, the sample derived from the subject is a whole blood sample.
[00042] In some aspects, the immunomodulatory disease-modifying therapeutic agent is selected from an interferon beta (IFNP) agent; a monoclonal antibody (mAb); a sphingosine 1 -phosphate receptor modulator; an anthracenedione antineoplastic; a pyrimidine synthesis inhibitor; a polymer of glutamic acid, lysine, alanine, and tyrosine; a fumarate agent; and an antimetabolite.
[00043] In some aspects, the immunomodulatory disease-modifying therapeutic agent is selected from the group consisting of ocrelizumab (Ocrevus®) (Roche), fmgolimod (Gilenya®) (Novartis), dimethyl fumarate (Tecfidera®) (Biogen), diroximel fumarate (Vumerity®) (Alkermes/Biogen), teriflunomide (Aubagio®) (Genzyme), siponimod (Mayzent®) (Novartis), cladribine (Mavenclad®) (Merck), alemtuzumab (Lemtrada®) (Sanofi-Aventis), mitoxantrone (Novantrone®), and natalizumab (Tysabri®) (Biogen).
[00044] In some aspects, the IFNP agent is selected from AVONEX® (interferon beta- la), BETASERON® (interferon beta-lb), EXTAVIA® (interferon beta-lb), PLEGRIDY® (peginterferon beta-la), and REBIF® (interferon beta-la). [00045] In some aspects, the mAb is selected from KESIMPTA® (ofatumumab), LEMTRADA® (alemtuzumab), OCREVUS® (ocrelizumab), and TYSABRI® (natalizumab). In some aspects, the sphingosine 1 -phosphate receptor modulator is selected from GILENYA® (fmgolimod), MAYZENT® (siponimod), PONVORY™ (ponesimod), and ZEPOSIA® (ozanimod). In some aspects, the anthracenedione antineoplastic is NOVANTRONE® (mitoxantrone). In some aspects, the pyrimidine synthesis inhibitor is AUBAGIO® (teriflunomide). In some aspects, the polymer of glutamic acid, lysine, alanine, and tyrosine is selected from COPAXONE® (glatiramer acetate), GLATOPA® (glatiramer acetate), and Glatiramer Acetate Injection (glatiramer acetate). In some aspects, the fumarate agent is BAFIERTAM™ (monomethyl fumarate), Dimethyl Fumarate (dimethyl fumarate), TECFIDERA® (dimethyl fumarate), or VUMERITY® (diroximel fumarate). In some aspects, the antimetabolite is MAVENCLAD® (cladribine).
[00046] In some aspects, the invention features a method further comprising administering an additional therapeutic agent to the subject. In some aspects, the additional therapeutic agent is a corticosteroid. In other aspects, the additional therapeutic agent is selected from SOLU-MEDROL® (methylprednisolone) or DELTASONE® (prednisone).
[00047] In some aspects, the additional therapeutic agent is a symptom managing agent for treatment of one or more symptoms of MS.
[00048] In some aspects, the symptom is a dysfunctional bladder and the symptom managing agent is selected from BOTOX® (onabotulinumtoxin A), DDAVP Nasal Spray (desmopressin), DETROL® (tolterodine), DITROPAN® (oxybutynin), DITROPAN XL®, ENABLEX® (darifenacin), FLOMAX® (tamsulosin), Prazosin, MYRBETRIQ® (mirabegron), OXYTROL® (oxybutynin), TOFRANIL (imipramine), and VESICARE (solifenacin succinate).
[00049] In some aspects, the symptom is a bladder infection and the symptom managing agent is selected from BACTRIM®, SEPTRA® (sulfamethoxazole), CIPO® (ciprofloxacin), LEVAQUIN® (levofloxacin), MACRODANTIM® (nitrofurantoin), HIPREX® (methenamine), and PYRIDIUM® (phenazopy ri dine) .
[00050] In some aspects, the symptom is a bowel dysfunction and the symptom managing agent is selected from COLACE® (docusate), DULCOLAX® (bisacodyl), ENEMEEZ® (docusate stool softener laxative), FLEET ENEMA® (sodium phosphate), a mineral oil, METAMUCIL® (psyllium hydrophilic musilloid), Phillips® Milk of Magnesia (magnesium hydroxide), and Sani-Supp® suppository (glycerin).
[00051] In some aspects, the symptom is depression and the symptom managing agent is an antidepressant. In some aspects, the antidepressant is selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), a norepinephrine dopamine reuptake inhibitor (NDR1), a serotonin partial agonist and reuptake inhibitor (SPARI), a serotonin antagonist and reuptake inhibitor (SARI), a monoamine oxidase inhibitor (MAOI), a N-methyl-d-aspartic acid (NMDA) antagonist, and noradrenergic and specific serotonergic antidepressant (NASSA). In some aspects, the antidepressant is selected from CELEXA® (citalopram), CYMBALTA® (duloxetine hydrochloride), EFFEXOR® (velafaxine), PAXIL® (paroxetine), PROZAC® (fluoxetine), WELLBUTRIN® (bupropion), and ZOLOFT® (sertraline).
[00052] In some aspects, the symptom is dizziness and/or vertigo and the symptom managing agent is ANTIVERT® (meclizine). In some aspects, the symptom is pseudobulbar affect and the symptom managing agent is NUEDEXTA® (dextromethorphan and quinidine). In some aspects, the symptom is fatigue and the symptom managing agent is selected from ADDERALL® (dextroamphetamine and amphetamine), amantadine, PRO VIGIL® (modafinil), PROZAC® (fluoxetine), and RITALIN® (methylphenidate). In some aspects, the symptom is itching and the symptom managing agent is VISTARIL® (hydroxyzine).
[00053] In some aspects, the symptom is pain and the symptom managing agent is selected from CYMBALTA® (duloxetine), EFFEXOR® (venlafaxine), ELAVIL® (amitriptyline), LAMICTAL® (lamotrigine), LYRICA® (pregabalin), NEURONTIN® (gabapentin), PAMELOR® (nortriptyline HCL), AVENTYL® (nortriptyline), TEGETRO®L (carbamazepine), and TRILEPTAL® (oxcarbazepine).
[00054] In some aspects, the symptom is a sexual problem and the symptom managing agent is selected from CIALIS® (tadalafil), LEVITRA® (vardenafil), MUSE® (alprostadil), PROSTIN VR® (alprostadil), STENDRA® (avanafil), and VIAGRA® (sildenafil).
[00055] In some aspects, the symptom is spasticity and the symptom managing agent is selected from baclofen, BOTOX® (onabotulinumtoxin A), DANTRIUM® (dantrolene), KLONOPIN® (clonazepam), VALIUM® (diazepam), and ZANAFLEX® (tizanidine). [00056] In some aspects, the symptom is a tremor and the symptom managing agent is selected from LANIAZID® (isoniazid) and KLONOPIN® (clonazepam). In some aspects, the symptom is difficulty walking and the symptom managing agent is AMPYRA® (dalfampridine).
[00057] In some aspects, the MS is a clinically isolated syndrome (CIS). In some aspects, the MS is a relapsing-remitting MS (RRMS). In some aspects, the MS is a primary progressive MS (PPMS). In some aspects, the MS is a secondary progressive MS (SPMS).
[00058] Both the foregoing summary and the following description of the drawings and detailed description are exemplary and explanatory. They are intended to provide further details of the disclosure, but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the disclosure.
BRIEF DESCRIPTION OF THE FIGURES
[00059] Figure 1 (FIG. 1) is a schematic illustration describing the analysis pipeline used in the experiments described in Example 2.
[00060] Figure 2A (FIG. 2A) is a Manhattan plot for the meta-analyzed GWAS summary statistics of the three Group A cohorts and three Group B cohorts described in Example 2.
[00061] Figure 2B (FIG. 2B) is a LocusZoom plot of top GWAS hit and nearby SNPs described in Example 2.
[00062] Figure 3 (FIG. 3) is a Manhattan plot for the gene-based tests of association, calculated from SNP summary statistics and p-values.
[00063] Figure 4A (FIG. 4A) is a 2-Sample Mendelian randomization scatterplot visualization for associations between Telomere Length and MS AAO.
[00064] Figure 4B (FIG. 4B) is a 2-Sample Mendelian randomization scatterplot visualization for associations between Age at Puberty and MS AAO.
DETAILED DESCRIPTION
[00065] The present invention in based, at least in part, on the discovery of polymorphic alleles that are associated with risk of MS progression (e.g., in terms of T2LVC) or age-at-onset (AAO) for MS. In particular, it was discovered that a C allele at polymorphism rs4962725 (SEQ ID NO: 1) in an intron of the C-terminal binding protein 2 (CTBP2) gene was associated with an increased risk of MS progression (e.g., in terms of rate of T2LVC). One equivalent allele (i.e., surrogate allele) was identified to be in linkage disequilibrium with polymorphism rs4962725C: an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6). Subjects having an increased risk of MS progression can be treated according to the methods disclosed herein, e.g., by administering a disease-modifying therapeutic agent (DMT), e.g., an immunomodulatory DMT, to the subject.
[00066] Additionally, an A allele at polymorphism rs3129882 (SEQ ID NO: 2) in major histocompatibility complex class II DR alpha (HLA-DRA) was associated with a decreased risk of developing an early AAO for MS; subjects with one copy of the rs3129882A allele experienced onset of MS about 1 .24 years later than subjects with the rs3129882G allele. Conversely, a G allele at polymorphism rs3091826 (SEQ ID NO: 3) located in eyes absent homolog 2 (EYA2) was associated with an increased risk of developing an early AAO for MS; subjects with one copy of the rs3091826G allele experienced onset of MS about 3 year earlier than subjects with a rs3091826A or rs3091826T allele. Two equivalent alleles (i.e., surrogate alleles) in linkage disequilibrium with polymorphism rs3091826G were also identified: a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5). Additionally, a T allele at polymorphism rs28672722 (SEQ ID NO: 9), or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); a T allele at polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) were associated with an earlier AAO. Subjects having a risk of an early onset of MS may be prophylactically treated according to the methods disclosed herein to prevent or reduce the likelihood of developing MS, e.g., by administering a DMT, e.g., an immunomodulatory DMT, to the subject.
[00067] Multiple sclerosis (MS) is a potentially disabling disease of the brain, optic nerves and spinal cord (central nervous system). In MS, the immune system attacks the protective sheath (myelin) that covers nerve fibers and causes communication problems between the brain and the rest of the body Eventually, the disease can cause permanent damage or deterioration of the nerve fibers. is no cure for multiple sclerosis (MS). Early treatment improves long-term health and wellbeing by slowing down the buildup of irreversible damage and reducing the number of relapses people experience, and therefore the ability to target treatment to patient populations having an increased risk of MS progression is highly beneficial.
[00068] Stages of MS: there are four stages of MS: (1) Clinically isolated syndrome (CIS): This is the first episode of symptoms caused by inflammation and damage to the myelin covering on nerves in the brain or spinal cord. (2) Relapsing-remitting MS (RRMS): The relapsing-remitting type of MS generally follows a predictable pattern, with periods in which symptoms worsen and then improve. Eventually, it may progress to secondary-progressive MS. Subjects with RRMS have flare-ups (relapses) of MS, and between the relapses, they have periods of remission. (3) Secondaryprogressive MS (SPMS): RRMS can progress into a more aggressive form of the disease. Some subjects with RRMS will go on to develop SPMS. This generally happens within 10 to 25 years of the first diagnosis. In SPMS, subjects may still experience relapses, and these are then followed by partial recoveries or periods of remission, but the disease doesn’t disappear between cycles. Instead, it steadily worsens. (4) Primary-progressive MS (PPMS): Approximately 10% to 15% of people receive a diagnosis of a relatively uncommon form of the disease, called PPMS. This form of MS is characterized by slow and steady disease progression with no remission periods.
[00069] Disease modifying therapies (DMTs) are not a cure for MS, but they can reduce how many relapses a subject has and how serious they are. They can also slow down the damage caused by relapsing multiple sclerosis that builds up over time. Thus, identifying subjects at risk for MS progression, and then targeting this patient population for treatment, is an efficient use of resources which can improve and prolong the quality of life of MS subjects.
[00070] Early onset of MS: Subjects of any age can develop MS, although subjects with MS tend to have their first symptoms between the ages of 20 and 40. Early detection of MS is critical as early treatment of MS can help delay progression of the disease. While the disease is chronic, it is usually mild in most case at the beginning. Elowever, some subjects may become unable to walk, have abnormal sensation and loss of balance, and the disease may also affect memory as the disease progresses. Treatment with MS medications has repeatedly shown to stop this progression. Thus, the ability to identify patient populations at risk of early onset of MS can, and then target these patient populations for treatment, is highly beneficial as early intervention and treatment can improve and prolong the quality of life of MS subjects. I. Therapeutic Methods
[00071] The present invention provides methods of treating a subject suffering from MS, such as CIS, RRMS, PPMS, SPMS. The methods of the invention include administering a therapy (e g., an immunomodulatory DMT agent) to a subject based on the patient’s genotype at one or more genetic polymorphisms described herein (e.g., a polymorphism selected from rs4962725 (SEQ ID NO: 1); rs3129882 (SEQ ID NO: 2); rs3091826 (SEQ ID NO: 3); rs28672722 (SEQ ID NO: 9); rs37411 (SEQ ID NO: 10), and/or a polymorphism that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), rs3129882 (SEQ ID NO: 2), rs3091826 (SEQ ID NO: 3), rs28672722 (SEQ ID NO: 9), and/or rs37411 (SEQ ID NO: 10)). Exemplary polymorphisms are shown in Table 1.
[00072] The rs4962725 (SEQ ID NO: 1) polymorphism is located within an intron of the C-terminal binding protein 2 (CTBP2)' gene. The rs3129882 (SEQ ID NO: 2) polymorphism is located within an intron of the major histocompatibility complex class II DR alpha (HLA-DRA) gene. The rs3091826 (SEQ ID NO: 3) polymorphism is located within an intron of the eyes absent homolog 2 (EYA2) gene. The rs28672722 (SEQ ID NO: 9) polymorphism is located within the HLA-DQB1- AS1 gene, and the rs37411 (SEQ ID NO: 10) polymorphism is located within the LOC105375167 gene. The rsl 1755689 (SEQ ID NO: 11) polymorphism is located within the HLA-DQA1 gene, and the rs28359884 (SEQ ID NO: 12) polymorphism is intergenic.
[00073] For example, in one aspect, the disclosure provides a method of treating a subject suffering from MS, the method including administering to the subject a therapy including a DMT agent (e g., an immunomodulatory DMT agent), wherein the genotype of the subject has been determined to include one or more of (a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (d) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (e) a T allele at polymorphism rs37411 (SEQ ID NO: 10), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (f) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (g) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12). In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) is polymorphism rsl0633091 (SEQ ID NO: 6). In some embodiments, the equivalent allele is an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6).
[00074] In another example, the disclosure provides a method of treating a subject suffering from MS, the method including: (a) determining in a sample derived from a subject suffering from MS the genotype at one or more of (i) polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression; and/or (ii) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or each equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of early onset of MS; (iii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of a G allele at polymorphism rs3091826 (SEQ ID NO: 3), or each equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), indicates that the subject has an increased risk of early onset of MS; (iv) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of a T allele at polymorphism rs28672722 (SEQ ID NO: 9), or each equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), indicates that the subject has an increased risk of early onset of MS; (v) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of a T allele at polymorphism rs37411 (SEQ ID NO: 10), or each equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), indicates that the subject has an increased risk of early onset of MS; (vi) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or each equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), indicates that the subject has an increased risk of early onset of MS; (vii) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or each equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), indicates that the subject has an increased risk of early onset of MS, and (b) administering a therapy including a DMT agent (e.g., an immunomodulatory DMT agent) to the subject who has been identified as having an increased risk of MS progression and/or an increased risk of early onset of MS. In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) is polymorphism rs!0633091 (SEQ ID NO: 6). In some embodiments, the equivalent allele is an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6).
[00075] In another example, the disclosure features a method of preventing and/or reducing the likelihood of developing MS (e.g., an early onset of MS) for a subject, the method comprising administering to the subject a therapy comprising a DMT agent (e.g., an immunomodulatory DMT agent), wherein the genotype of the subject has been determined to comprise one or more of (a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (d) a T allele at polymorphism rs37411 (SEQ ID NO: 10), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (e) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (f) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[00076] In another example, the disclosure features a method of preventing and/or reducing the likelihood of developing MS in a subject (e.g., an early onset of MS), the method comprising: (a) determining in a sample derived from the subject the genotype at one or more of (i) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iii) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iv) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iv) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); and/or (iv) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); and (b) administering a therapy comprising a DMT agent (e g , an immunomodulatory DMT agent) to the subject who has been identified as having an increased risk of developing MS (e.g., an early onset of MS). [00077] In another example, the disclosure features a method of selecting a therapy for preventing or reducing the likelihood of developing MS in a subject (e.g., an early onset of MS), the method comprising: (a) determining in a sample derived from a subject the genotype at (i) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iii) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iv) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iv) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); and/or (iv) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); and (b) selecting a therapy comprising a DMT agent (e.g., an immunomodulatory DMT agent) for the subject who has been identified as having an increased risk of developing MS (e.g., an early onset of MS).
[00078] In some examples, the subject is at an increased risk of developing MS (e.g., an early onset of MS) if the genotype of the subject comprises one or more of a (a) G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), compared to a subject whose genotype does not comprise a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (d) T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), compared to a subject whose genotype does not comprise a T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (e) G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), compared to a subject whose genotype does not comprise a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (f) A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), compared to a subject whose genotype does not comprise an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12). [00079] In some examples, the disclosure encompasses a method of identifying a subject at an increased risk of developing MS (e.g., an early onset of MS) if the genotype of the subject comprises one or more of a (a) G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), compared to a subject whose genotype does not comprise a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), compared to a subject whose genotype does not comprise an G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), compared to a subject whose genotype does not comprise a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); and/or (d) T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), compared to a subject whose genotype does not comprise a T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (e) G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), compared to a subject whose genotype does not comprise a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (f) A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), compared to a subject whose genotype does not comprise an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[00080] In another example, the disclosure provides a method of treating a subject who has been previously determined to have one or more of a (a) G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (d) T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (e) G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (f) A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), thereby identifying the subject as having a risk of developing MS (e g., an early onset of MS), and who optionally has been previously diagnosed with MS, the method including administering to the subject a therapy including a DMT agent (e.g., an immunomodulatory DMT agent). In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the equivalent allele is a C allele at polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
[00081] In another example, the disclosure provides a method of treating a subject who has been previously determined to have one or more of a (a) G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (d) T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (e) G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (f) A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), thereby identifying the subject as having a risk of developing MS (e.g., an early onset of MS), the method including administering to the subject a therapy including a DMT agent (e.g., an immunomodulatory DMT agent). In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the equivalent allele is a C allele at polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
[00082] In another example, the disclosure provides a method of monitoring and/or treating a subject having a risk of developing an early onset of MS, the method including: (a) determining in a sample derived from the subject the genotype at (i) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS; (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iii) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iv) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iv) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iv) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (b) monitoring the subject identified as having a risk of developing an early onset of MS for one or more symptoms of MS; (c) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and (d) administering a therapy including a DMT agent (e.g., an immunomodulatory diseasemodifying therapeutic agent) to the subject diagnosed with MS. In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the equivalent allele is a C allele at polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
Figure imgf000039_0001
Figure imgf000040_0001
A = adenine; T = thymine; C = cytosine; G = guanine
Subjects
[000831 The present disclosure provides for methods of treating a subject (e.g., a human) with one or more (e.g., 1, 2, 3, 4, 5, 6, etc.) of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a C allele at polymorphism rs3092737 (SEQ ID NO: 4); (v) a C allele at polymorphism rs3092258 (SEQ ID NO: 5); (vi) an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6); (vii) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (viii) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (xi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (x) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (xi) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (xii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (xiii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (xiv) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (xv) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (xvi) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and (xvii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12). It is within the scope of the invention that the subject to be treated by the methods described herein includes any one of the aforementioned genotypes or any combination of the aforementioned genotypes.
[00084] As is demonstrated herein, a subject with a C allele at polymorphism rs4962725 (SEQ ID NO: 1) (also referred to herein as “rs4962725C”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), e.g., an insertion of AG at polymorphism rs 10633091 (SEQ ID NO: 6) (also referred herein as “rsl0633091CAG”), is at an increased risk of MS progression (e.g., in terms of rate of T2LVC), compared to a subject whose genotype does not contain a C allele (e.g., a subject containing a T allele) at polymorphism rs4962725 (SEQ ID NO: 1), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1). To be clear, the rs!0633091CAG allele is an insertion of an AG following the C located at chromosome (chr) 10, nucleotide position 125044448 (i.e., chrlO: 125044448), e.g., relative to Genome Reference Consortium Human Build 38 patch release 13 (GRCh38.pl3). In other words, the two alleles for polymorphism rsl0633091 are CAG (i.e., an insertion of AG) and C, of which CAG is the surrogate for rs496272C. Another way of describing this polymorphism is to start on the next position, i.e., chrlO: 125044449, in which the two alleles for this polymorphism are AG/2 bp-deletion. By way of example, the nucleotide sequence of variable SEQ ID NO: 6 (e.g., when AG is absent) may be CTCTGACTTTTCATCCGGAGTTAACCCACATGTGCTCAGGCCACCTCAAA (SEQ ID NO: 7). In another example, the nucleotide sequence of variable SEQ ID NO: 6 (e.g., when AG is inserted) may be CTCTGACTTTTCATCCGGAGTTAACAGCCACATGTGCTCAGGCCACCTCAAA (SEQ ID NO: 8).
[00085] As is also demonstrated herein, a subject with a G allele at polymorphism rs3129882 (SEQ ID NO: 2) (also referred herein as “rs3129882G”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), is at risk of developing MS, such as an early age-at-onset (AAO) of MS, compared to a subject whose genotype does not contain a G allele (e.g., a subject containing an A allele) at polymorphism rs3129882 (SEQ ID NO: 2), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2).
[00086] As is also demonstrated herein, a subject with a G allele at polymorphism rs3091826 (SEQ ID NO: 3) (also referred herein as “rs3091826G”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5), is at risk of developing MS, such as an early AAO of MS, compared to a subject whose genotype does not contain a G allele (e.g., a subject containing an A or a T allele) at polymorphism rs3091826 (SEQ ID NO: 3), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3).
[00087] In some embodiments, the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6))-
[00088] In some embodiments, the subject has the following genotype: a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882.
[00089] In some embodiments, the subject has the following genotype: a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)).
[00090] In some embodiments, the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e g., an insertion of AG at polymorphism rsl 0633091 (SEQ ID NO: 6)); and a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882.
[00091] In some embodiments, the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5))
[00092] In some embodiments, the subject has the following genotype: a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882; and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)).
[00093] In some embodiments, the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882; and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)).
[00094] In some embodiments, the subject has the following genotype: a T allele at polymorphism rs28672722 (SEQ ID NO: 9), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722.
[00095] In some embodiments, the subject has the following genotype: a T allele at polymorphism rs37411 (SEQ ID NO: 10), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411.
[00096] Tn some embodiments, the subject has the following genotype: a G allele at rsl 1755689 (SEQ ID NO: 11), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11).
[00097] In some embodiments, the subject has the following genotype: an A allele at polymorphism rs28359884 (SEQ ID NO: 12), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[00098] In some embodiments, the subject has any one of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6)); (ix) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (x) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); (xi) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (xii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (xiii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (xiv) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[00099] Tn some embodiments, the subject has any two of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6)); (ix) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (x) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); (xi) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (xii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (xiii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (xiv) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[000100] In some embodiments, the subject has any three of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl 0633091 (SEQ ID NO: 6)); (ix) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (x) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs309I826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); (xi) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (xii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (xiii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (xiv) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[000101] In some embodiments, the subject has any four of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6)); (ix) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (x) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); (xi) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (xii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (xiii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (xiv) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[000102] In some embodiments, the subject has any five of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6)); (ix) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (x) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); (xi) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (xii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (xiii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (xiv) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[0001031 In some embodiments, the subject has six, seven, eight, nine, or ten of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); (ix) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (x) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); (xi) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (xii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (xiii) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (xiv) an equivalent allele at a polymorphisms in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[000104] In any of the preceding embodiments, the equivalent allele may be at an alternate single nucleotide polymorphism (SNP) that is in linkage disequilibrium with one or more of the selected SNPs described herein (e.g., rs4962725 (SEQ ID NO: 1); rs3129882 (SEQ ID NO: 2); rs3091826 (SEQ ID NO: 3)); rs28672722 (SEQ ID NO: 9); rs37411 (SEQ ID NO: 10); rsl 1755689 (SEQ ID NO: 11); and/or rs28359884 (SEQ ID NO: 12). In some embodiments, the equivalent allele that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1) is an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6). In some embodiments, the equivalent allele that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3) is a C allele at polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the equivalent allele that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3) is a C allele at polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the subject’s genotype may include a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the linkage disequilibrium is a D’ value or an r2 value. In some embodiments, the D’ measure between the selected SNP and the alternate SNP is > 0.60 (e.g., > 0.60, > 0.65, > 0.7, > 0.75, > 0.8, > 0.85, > 0.9, > 0.95, or higher). In some embodiments, the D’ value between the selected SNP and the alternate SNP is >0.70, > 0.80, or > 0.90. In some embodiments, the D’ value between the selected SNP and the alternate SNP is 1.0. In some embodiments, the r2 value between the selected SNP and the alternate SNP is > 0.60 (e.g., > 0.60, > 0.65, > 0.7, > 0.75, > 0.8, > 0.85, > 0.9, > 0.95, or higher). In some embodiments the r2 value between the selected SNP and the alternate SNP is > 0.70, > 0.80, or > 0.90. In some embodiments, the r2 value between the selected SNP and the alternate SNP is 1.0. In any of the preceding methods, the equivalent allele may be the minor allele or the major allele. In some instances, the equivalent allele is the minor allele. In other instances, the equivalent allele is the major allele.
[000105] In some embodiments, the genotype of the subject is derived from a sample of the subject, such as blood, plasma, serum, urine, saliva, stool, pleural fluid, lymphatic fluid, sputum, ascites, prostatic fluid, cerebrospinal fluid (CSF), or any other bodily secretion or derivative thereof. In some embodiments, the sample derived from the subject is a whole blood sample, a serum sample, a plasma sample, or a combination thereof. In some embodiments, the sample derived from the subject is a whole blood sample. In some embodiments, the sample derived from a subject is a serum sample. In some embodiments, the sample derived from a subject a plasma sample.
[000106] The genotype of a subject can be determined using any of the methods or assays described herein or that are known in the art.
Administration
[000107] The present disclosure provides for methods of treating a subject (e.g., a human) described herein with at least one DMT agent, such as any DMT agent described herein (e.g., an immunomodulatory DMT). The subject may be further administered one or more additional therapeutic agents in combination with the at least one DMT agent. Additional therapeutic agents, such as corticosteroids and symptom managing agents, may also be administered to the subject and are described herein.
[000108] In some embodiments, the methods of the invention include administering to the subject (e.g., a human) a therapy including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable DMT agent (e.g., an immunomodulatory DMT agent), such as any of the DMT agents described herein.
[000109] In some embodiments, the methods of the invention include administering to the subject (e.g., a human) a combinatorial therapy including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable DMT agent (e.g., an immunomodulatory DMT agent), such as any of the DMT agents described herein, and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable corticosteroid, such as any of the corticosteroids described herein.
[000110] In some embodiments, the methods of the invention include administering to the subject (e.g., a human) a combinatorial therapy including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable DMT agent (e.g., an immunomodulatory DMT agent), such as any of the DMT agents described herein, and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable symptom managing agent, such as any of the symptom managing agents described herein.
[000111] In some embodiments, the methods of the invention include administering to the subject (e.g., a human) a combinatorial therapy including one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable DMT agent (e.g., an immunomodulatory DMT agent), such as any of the DMT agents described herein, and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable corticosteroid, such as any of the corticosteroids described herein, and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of any suitable symptom managing agent, such as any of the symptom managing agents described herein.
[000112] In some embodiments, the methods of the invention may include administering the corticosteroid and/or symptom managing agent either before or after administration of the DMT agent (e.g., an immunomodulatory DMT agent). In some embodiments, the corticosteroid and/or symptom managing agent is administered to the subject about 1 minute, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 40 hours, about 44 hours, or about 48 hours prior to administering the DMT agent (e.g., an immunomodulatory DMT agent).
[000113] In some embodiments, the corticosteroid and/or symptom managing agent is administered to the subject about 1 minute, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours about 24 hours, about 27 hours, about 30 hours, about 33 hours, about 36 hours, about 40 hours, about 44 hours, or about 48 hours after administering the DMT agent (e.g., an immunomodulatory DMT agent).
[000114] In some embodiments, the methods of the invention may include administering the corticosteroid and/or symptom managing agent either before or after administration of the DMT agent (e.g., an immunomodulatory DMT agent). In some embodiments, the corticosteroid and/or symptom managing agent is administered to the subject 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 15 hours, 18 hours, 21 hours 24 hours, 27 hours, 30 hours, 33 hours, 36 hours, 40 hours, 44 hours, or 48 hours prior to administering the DMT agent (e.g., an immunomodulatory DMT agent).
[000115] In some embodiments, the corticosteroid and/or symptom managing agent is administered to the subject 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 15 hours, 18 hours, 21 hours 24 hours, 27 hours, 30 hours, 33 hours, 36 hours, 40 hours, 44 hours, or 48 hours after administering the DMT agent (e.g., an immunomodulatory DMT agent).
[000116] Any suitable DMT agent (e.g., immunomodulatory DMT agent), corticosteroid, and/or symptom managing agent described herein may be administered to a subject described herein (e.g., a subject with a C allele at polymorphism rs4962725 (SEQ ID NO: 1); a G allele at polymorphism rs3129882 (SEQ ID NO: 2); a G allele at polymorphism rs3091826 (SEQ ID NO: 3), a C allele at polymorphism rs3092737 (SEQ ID NO: 4); a C allele at polymorphism rs3092258 (SEQ ID NO: 5); an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6); and/or an equivalent allele that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), rs3129882 (SEQ ID NO: 2), and/or rs3091826 (SEQ ID NO: 3)) by any suitable means, including parenteral, topical, subcutaneous, intraperitoneal, intrapulmonary, intranasal, and/or intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Intrathecal administration is also contemplated. In addition, the DMT agent (e.g., an immunomodulatory DMT agent), corticosteroid, and/or symptom managing agent described herein may be administered to a subject described herein (e g., a subject with a C allele at polymorphism rs4962725 (SEQ ID NO: 1); a G allele at polymorphism rs3129882 (SEQ ID NO: 2); a G allele at polymorphism rs3091826 (SEQ ID NO: 3); and/or an equivalent allele at a polymorphism that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), rs3129882 (SEQ ID NO: 2), and/or rs3091826 (SEQ ID NO: 3)) by pulse infusion, e.g., with declining doses of the DMT agent, corticosteroid, and/or symptom managing agent.
Immunomodulatory disease-modifying therapeutic (DMT) agents
[000117] In some embodiments, the methods of the invention include administering to the subject having one or more of the genotypes described herein (e.g., a subject with a C allele at polymorphism rs4962725 (SEQ ID NO: 1); a G allele at polymorphism rs3129882 (SEQ ID NO: 2); a G allele at polymorphism rs3091826 (SEQ ID NO: 3); a T allele at orphism rs28672722 (SEQ ID NO: 9); a T allele at polymorphism rs37411 (SEQ ID NO: 10); a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); an A allele at polymorphism rs28359884 (SEQ ID NO: 12); and/or an equivalent allele at a polymorphism that is in linkage disequilibrium with rs4962725, rs3129882, rs3091826, rs28672722, rs37411, rsl 1755689, and/or rs28359884) an immunomodulatory DMT agent. Any suitable immunomodulatory DMT agent or combination of immunomodulatory DMT agents may be administered. Immunomodulatory DMT agent(s) include one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more) of the following: an interferon beta (IFNP) agent; a monoclonal antibody (mAb); a sphingosine 1-phosphate receptor modulator; an anthracenedione antineoplastic; a pyrimidine synthesis inhibitor; a polymer of glutamic acid, lysine, alanine, and tyrosine; a fumarate agent; and an antimetabolite. [000118] In some embodiments, the immunomodulatory DMT agent is an IFNP agent. In some embodiments, the IFNP agent is selected from AVONEX® (interferon beta-la), BETASERON® (interferon beta-lb), EXTAVIA® (interferon beta-lb), PLEGRIDY® (peginterferon beta-la), and REBIF® (interferon beta- la). Any generic drug thereof is also envisioned.
[000119] In some embodiments, the immunomodulatory DMT agent is a mAb. In some embodiments, the mAb is an anti-CD20 antibody (e.g., KESIMPTA® (ofatumumab). In some embodiments, the mAb is an anti-CD52 antibody (e.g., LEMTRADA® (alemtuzumab) or OCREVUS® (ocrelizumab)). In some embodiments, the mAb is an anti-a4pl integrin (very late antigen-4) antibody (e.g , TYSABRI® (natalizumab)). In some embodiments, the mAb is selected from KESIMPTA® (ofatumumab), LEMTRADA® (alemtuzumab), OCREVUS® (ocrelizumab), and TYSABRI® (natalizumab). Any generic drug thereof is also envisioned.
[000120] In some embodiments, the immunomodulatory DMT agent is a sphingosine 1 -phosphate receptor modulator. In some embodiments, the sphingosine 1 -phosphate receptor modulator is selected from GlLENYA® (fingolimod), MAYZENT® (siponimod), PONVORY™ (ponesimod), and ZEPOSIA® (ozanimod). Any generic drug thereof is also envisioned.
[000121] In some embodiments, the immunomodulatory DMT agent is an anthracenedione antineoplastic. In some embodiments, the anthracenedione antineoplastic is NOVANTRONE® (mitoxantrone). Any generic drug thereof is also envisioned.
[000122] In some embodiments, the immunomodulatory DMT agent is a pyrimidine synthesis inhibitor. In some embodiments, the pyrimidine synthesis inhibitor is AUBAGIO® (teriflunomide). Any generic drug thereof is also envisioned.
[000123] In some embodiments, the immunomodulatory DMT agent is a polymer of glutamic acid, lysine, alanine, and tyrosine. In some embodiments, the polymer of glutamic acid, lysine, alanine, and tyrosine is selected from COPAXONE® (glatiramer acetate), GLATOPA® (glatiramer acetate), and Glatiramer Acetate Injection (glatiramer acetate). Any generic drug thereof is also envisioned.
[000124] In some embodiments, the immunomodulatory DMT agent is a fumarate agent. In some embodiments, the fumarate agent is selected from BAFIERTAM™ (monomethyl fumarate), Dimethyl Fumarate (dimethyl fumarate), TECFIDERA® (dimethyl fumarate), and VUMERITY® (diroximel fumarate). [000125] In some embodiments, the immunomodulatory DMT agent is an antimetabolite. In some embodiments, the antimetabolite is MAVENCLAD® (cladribine). Any generic drug thereof is also envisioned.
[000126] In some embodiments, the present invention includes an immunomodulatory DMT agent for use in treating a subject suffering from MS, wherein the genotype of the subject has been determined to include a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6)). The presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)) indicates that the subject has an increased risk of MS progression.
[000127] In some embodiments, the present invention includes an immunomodulatory DMT agent for use in treating a subject who has been previously diagnosed with MS and who has been previously determined to have one or more of a (i) G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882, thereby identifying the subject as having a risk of developing MS (e.g., an early onset of MS); (ii) G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)), thereby identifying the subject as having a risk of developing MS, (e.g., an early onset of MS); (iii) T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), thereby identifying the subject as having a risk of developing MS, (e.g., an early onset of MS); (iv) T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), thereby identifying the subject as having a risk of developing MS, (e.g., an early onset of MS); (v) G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), thereby identifying the subject as having a risk of developing MS, (e g., an early onset of MS); and/or (vi) A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), thereby identifying the subject as having a risk of developing MS, (e.g., an early onset of MS). The presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 indicates that the subject has an increased risk of developing MS, such as an early onset of MS. In addition, the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)) indicates that the subject has an increased risk of developing MS, such as an early onset of MS. The presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) and/or polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of developing MS, such as an early onset of MS. The presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of developing MS, such as an early onset of MS. Finally, the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
[000128] In some embodiments, the present invention includes an immunomodulatory DMT agent for use in preventing or reducing the likelihood of developing MS in a subject who has been previously determined to have one or more of a (i) G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (ii) G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); (iii) T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (iv) T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (v) G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (vi) A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12). The presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 indicates that the subject has an increased risk of developing MS, such as an early onset of MS. In addition, the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)) indicates that the subject has an increased risk of developing MS, such as an early onset of MS. The presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) and or polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of developing MS, such as an early onset of MS. The presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of developing MS, such as an early onset of MS. Finally, the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of developing MS, such as an early onset of MS.
[000129] In some embodiments, the present invention includes the use of an effective amount of an immunomodulatory DMT agent in the manufacture of a medicament for use in treating a subject suffering from MS, wherein the subject has been determined to include one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or seventeen of the following alleles: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1), (ii) an equivalent allele that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), (iii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), (iv) an equivalent allele that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2), (v) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), (vi) an equivalent allele that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3), (vii) a C allele at polymorphism rs3092737 (SEQ ID NO: 4), (viii) a C allele at polymorphism rs3092258 (SEQ ID NO: 5), (ix) an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)), (x) a T allele at polymorphism rs28672722 (SEQ ID NO: 9), (xi) an equivalent allele that is in linkage disequilibrium with rs28672722 (SEQ ID NO: 9), (xii) a T allele at polymorphism rs37411 (SEQ ID NO: 10), (xiii) an equivalent allele that is in linkage disequilibrium with rs37411 (SEQ ID NO: 10), (xiv) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), (xv) an equivalent allele that is in linkage disequilibrium with rsl 1755689 (SEQ ID NO: 11), (xvi) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), and (xvii) an equivalent allele that is in linkage disequilibrium with rs28359884 (SEQ ID NO: 12).
[000130] In some embodiments, the present invention includes a composition including an effective amount of an immunomodulatory DMT agent for use in a method of treating a subject suffering from MS, wherein the subject has been determined to include one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or seventeen of the following alleles: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1), (ii) an equivalent allele that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), (iii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), (iv) an equivalent allele that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2), (v) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), (vi) an equivalent allele that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3), (vii) a C allele at polymorphism rs3092737 (SEQ ID NO: 4), (viii) a C allele at polymorphism rs3092258 (SEQ ID NO: 5), (ix) an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)), (x) a T allele at polymorphism rs28672722 (SEQ ID NO: 9), (xi) an equivalent allele that is in linkage disequilibrium with rs28672722 (SEQ ID NO: 9), (xii) a T allele at polymorphism rs37411 (SEQ ID NO: 10), (xiii) an equivalent allele that is in linkage disequilibrium with rs37411 (SEQ ID NO: 10), (xiv) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), (xv) an equivalent allele that is in linkage disequilibrium with rsl 1755689 (SEQ ID NO: 11), (xvi) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), and (xvii) an equivalent allele that is in linkage disequilibrium with rs28359884 (SEQ ID NO: 12). The composition may be a pharmaceutical composition.
Additional Therapeutic Agents
[000131] In addition to the administration one or more of the DMT agents (e.g., immunomodulatory DMT agents) described above to a subject described above, administration of additional therapeutic agent(s) is also envisioned by the present invention. In some embodiments, the methods of the invention include administering to the subject one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) additional therapeutic agents.
[000132] In some embodiments, the one or more additional therapeutic agent is a corticosteroid. The corticosteroid may be administered to the subject orally, intravenously, or by any other suitable administration route. Any suitable corticosteroid may be used (e.g., dexamethasone, methylprednisolone, prednisone, prednisolone, betamethasone, hydrocortisone, and the like). In some embodiments, the corticosteroid is selected from SOLU-MEDROL® (methylprednisolone) or DELTASONE® (prednisone). Any generic drug thereof is also envisioned.
[000133] In some embodiments, the one or more additional therapeutic agents is a symptom managing agent for treatment of one or more symptoms of MS (e.g., a dysfunctional bladder, a bladder infection, a bowel dysfunction, depression, dizziness, vertigo, pseudobulbar affect, fatigue, itching, pain, a sexual problem, spasticity, tremors, and/or difficulty walking).
[000134] In some embodiments, the symptom managing agent is one that treats a subject’s dysfunctional bladder. Any suitable symptom managing agent for a dysfunctional bladder may be used (e.g., onabotulinumtoxin A, desmopressin, tolterodine, oxybutynin, darifenacin, tamsulosin, mirabegron, oxybutynin, imipramine, solifenacin succinate, and any combination thereof). In some embodiments, the symptom managing agent for treating the subject’s dysfunctional bladder is selected from BOTOX® (onabotulinumtoxin A), DDAVP Nasal Spray (desmopressin), DETROL® (tolterodine), DTTROPAN® (oxybutynin), DTTROPAN XL®, ENABLEX® (darifenacin), FLOMAX® (tamsulosin), Prazosin, MYRBETRIQ® (mirabegron), OXYTROL® (oxybutynin), TOFRANIL® (imipramine), and VESICARE® (solifenacin succinate). Any generic drug thereof is also envisioned.
[000135] In some embodiments, the symptom managing agent is one that treats a subject’s bladder infection. Any suitable symptom managing agent for a bladder infection may be used (e.g., sulfamethoxazole, ciprofloxacin, levofloxacin, nitrofurantoin, methenamine, phenazopyridine, and any combination thereof). In some embodiments, the symptom managing agent for treating the subject’s bladder infection is selected from BACTRIM®, SEPTRA® (sulfamethoxazole), CIPO® (ciprofloxacin), LEVAQUIN® (levofloxacin), MACRODANTIM® (nitrofurantoin), HIPREX® (methenamine), and PYRIDIUM® (phenazopyridine). Any generic drug thereof is also envisioned.
[000136] In some embodiments, the symptom managing agent is one that treats a subject’s bowel dysfunction. Any suitable symptom managing agent for bowel dysfunction may be used (e.g., docusate, bisacodyl, docusate stool softener laxative, sodium phosphate, mineral oils, psyllium hydrophilic musilloid, magnesium hydroxide, glycerine, and any combination thereof). In some embodiments, the symptom managing agent for treating the subject’s bowel dysfunction is selected from COLACE® (docusate), DULCOLAX® (bisacodyl), ENEMEEZ® (docusate stool softener laxative), FLEET ENEMA® (sodium phosphate), a mineral oil, METAMUCIL® (psyllium hydrophilic musilloid), Phillips® Milk of Magnesia (magnesium hydroxide), and SANI-SUPP® suppository (glycerine). Any generic drug thereof is also envisioned.
[000137] In some embodiments, the symptom managing agent is one that treats a subject’s depression. In some embodiments, the symptom managing agent for treating the subject’s depression is an antidepressant, such as a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), a norepinephrine dopamine reuptake inhibitor (NDRI), a serotonin partial agonist and reuptake inhibitor (SPARI), a serotonin antagonist and reuptake inhibitor (SARI), a monoamine oxidase inhibitor (MAOI), a N- methyl-d-aspartic acid (NMDA) antagonist, and noradrenergic and specific serotonergic antidepressant (NASSA). Any suitable symptom managing agent for depression may be used (e.g., citalopram, duloxetine hydrochloride, venlafaxine, paroxetine, fluoxetine, fluoxetine, bupropion, sertraline, and any combination thereof). In some embodiments, the symptom managing agent for treating the subject’s depression (e.g., an antidepressant) is selected from CELEXA® (citalopram), CYMBALTA® (duloxetine hydrochloride), EFFEXOR® (enlafaxine), PAXIL® (paroxetine), PROZAC® (fluoxetine), WELLBUTRIN® (bupropion), and ZOLOFT® (sertraline). Any generic drug thereof is also envisioned.
[000138] In some embodiments, the symptom managing agent is one that treats a subject’s dizziness and/or vertigo. Any suitable symptom managing agent for dizziness and/or vertigo may be used (e.g., meclizine). In some embodiments, the symptom managing agent for treating the subject’s dizziness and/or vertigo is ANTIVERT® (meclizine). Any generic drug thereof is also envisioned.
[000139] In some embodiments, the symptom managing agent is one that treats a subject’s pseudobulbar affect. Any suitable symptom managing agent for pseudobulbar affect may be used (e.g., dextromethorphan, quinidine, and any combination thereof). In some embodiments, the symptom managing agent for treating the subject’s pseudobulbar affect is is NUEDEXTA® (dextromethorphan and quinidine). Any generic drug thereof is also envisioned.
[000140] In some embodiments, the symptom managing agent is one that treats a subject’s fatigue. Any suitable symptom managing agent for fatigue may be used (e.g., dextroamphetamine, amphetamine, modafinil, modafinil, fluoxetine, methylphenidate, and any combination thereof). In some embodiments, the symptom managing agent for treating the subject’s fatigue is selected from ADDERALL® (dextroamphetamine and amphetamine), amantadine, PRO VIGIL® (modafinil), PROZAC® (fluoxetine), and RITALIN® (methylphenidate). Any generic drug thereof is also envisioned.
[000141] In some embodiments, the symptom managing agent is one that treats a subject’s itchy skin. Any suitable symptom managing agent for itchiness may be used (e.g., hydroxyzine). In some embodiments, the symptom managing agent for treating a subject’s itchy skin is VISTARIL® (hydroxyzine). Any generic drug thereof is also envisioned. [000142] In some embodiments, the symptom managing agent is one that treats a subject’s pain. Any suitable symptom managing agent for pain may be used (e.g., duloxetine, venlafaxine, amitriptyline, lamotrigine, pregabalin, gabapentin, nortriptyline HCL, nortriptyline, carbamazepine, oxcarbazepine, and any combination thereof). In some embodiments, the symptom managing agent for treating the subject’s pain is selected from CYMBALTA® (duloxetine), EFFEXOR® (venlafaxine), ELAVIL® (amitriptyline), LAMICTAL® (lamotrigine), LYRICA® (pregabalin), NEURONTIN® (gabapentin), PAMELOR® (nortriptyline HCL), AVENTYL® (nortriptyline), TEGETRO® (carbamazepine), and TRILEPTAL® (oxcarbazepine). Any generic drug thereof is also envisioned.
[000143] In some embodiments, the symptom managing agent is one that treats a subject’s sexual problem (e.g., sexual impotence and erectile dysfunction). Any suitable symptom managing agent for a sexual problem may be used (e.g., tadalafil, vardenafd, alprostadil, avanafil, sildenafil, and any combination thereof). In some embodiments, the symptom managing agent for treating the subject’s sexual problem (e.g., sexual impotence or erectile dysfunction) is selected from CIALIS® (tadalafil), LEVITRA® (vardenafd), MUSE® (alprostadil), PROSTIN VR® (alprostadil), STENDRA® (avanafil), and VIAGRA® (sildenafil). Any generic drug thereof is also envisioned.
[000144] In some embodiments, the symptom managing agent is one that treats a subject’s spasticity. Any suitable symptom managing agent for spasticity may be used (e.g., onabotulinumtoxin A, dantrolene, clonazepam, diazepam, tizanidine, and any combination thereof). In some embodiments, the symptom managing agent for treating the subject’s spasticity is selected from baclofen, BOTOX® (onabotulinumtoxin A), DANTRIUM® (dantrolene), KLONOPIN® (clonazepam), VALIUM® (diazepam), and ZANAFLEX® (tizanidine). Any generic drug thereof is also envisioned.
[000145] In some embodiments, the symptom managing agent is one that treats a subject’s tremor. Any suitable symptom managing agent for tremors may be used (e.g., isoniazid, clonazepam, and any combination thereof). In some embodiments, the symptom managing agent for treating the subject’s tremor is selected from LANIAZID® (isoniazid) and KLONOPIN® (clonazepam). Any generic drug thereof is also envisioned.
[000146] In some embodiments, the symptom managing agent is one that treats a subject’s difficulty with walking. Any suitable symptom managing agent for walking difficulty may be used (e.g., dalfampridine). In some embodiments, the symptom managing agent for treating the subject’s difficulty with walking is AMPYRA® (dalfampridine). Any generic drug thereof is also envisioned.
[000147] In some embodiments, the methods of the invention include administering to the subject one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of the corticosteroids and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or more) of the symptom managing agents described herein.
II. Diagnostics
[000148] The present invention provides diagnostic methods of determining whether a subject is at risk of MS progression (e.g., in terms of rate of T2LVC, e.g., in a subject with CIS, RRMS, PPMS, or SPMS). Additionally, the present invention provides methods of selecting a therapy (e.g., a DMT agent (e.g., an immunomodulatory DMT agent)) for a subject based on the subject’s genotype at one or more genetic polymorphisms described herein (e.g., a polymorphism selected from rs4962725 (SEQ ID NO: 1), a polymorphism that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), rs3129882 (SEQ ID NO: 2), a polymorphism that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2), rs3091826 (SEQ ID NO: 3), a polymorphism that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3), rs28672722 (SEQ ID NO: 9), a polymorphism that is in linkage disequilibrium with rs28672722 (SEQ ID NO: 9), rs37411 (SEQ ID NO: 10), a polymorphism that is in linkage disequilibrium with rs37411 (SEQ ID NO: 10), rsl 1755689 (SEQ ID NO: 11), a polymorphism that is in linkage disequilibrium with rsl 1755689 (SEQ ID NO: 11), rs28359884 (SEQ ID NO: 12), a polymorphism that is in linkage disequilibrium with rs28359884 (SEQ ID NO: 12)). Exemplary polymorphisms are shown in Table 1. The selected therapy may be administered to the subject using the therapeutic methods described in Section II above.
[000149] The present invention further provides diagnostic methods of determining whether a subject is at risk of developing MS (e.g., an early onset of MS). Additionally, the present invention provides methods of selecting a therapy (e g., a DMT agent (e.g., an immunomodulatory DMT agent)) for a subject based on the subject’s genotype at one or more genetic polymorphisms described herein (e.g., a polymorphism selected from rs3129882 (SEQ ID NO: 2), rs3091826 (SEQ ID NO: 3), rs28672722 (SEQ ID NO: 9), rs37411 (SEQ ID NO: 10), and/or a polymorphism that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2) and/or rs3091826 (SEQ ID NO: 3) and/or rs28672722 (SEQ ID NO: 9) and/or rs37411 (SEQ ID NO: 10); and/or rsl 1755689 (SEQ ID NO: 11), and/or rs28359884 (SEQ ID NO: 12)). Exemplary polymorphisms are shown in Table 1. The selected therapy may be administered to the subject using the therapeutic methods described in Section II above.
[000150] The present invention further provides diagnostic methods of determining whether a subject is at risk of developing an early onset of MS (e.g., in terms of age-at-onset (AAO)). Additionally, the present invention provides methods of monitoring a subject determined to be at risk of developing an early onset of MS and selecting a therapy (e.g., a DMT agent (e.g., an immunomodulatory DMT agent)) for a subject based on the subject’s genotype at one or more genetic polymorphisms described herein (e.g., a polymorphism selected from rs3129882 (SEQ ID NO: 2); rs3091826 (SEQ ID NO: 3), rs28672722 (SEQ ID NO: 9), rs3741 1 (SEQ ID NO: 10), rsl 1755689 (SEQ ID NO: 11), rs28359884 (SEQ ID NO: 12), and/or a polymorphism that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2), and/or rs3091826 (SEQ ID NO: 3), rs28672722 (SEQ ID NO: 9), rs37411 (SEQ ID NO: 10), rsl 1755689 (SEQ ID NO: 11), and/or rs28359884 (SEQ ID NO: 12)). Exemplary polymorphisms are shown in Table 1. The selected therapy may be administered to the subject using the therapeutic methods described in Section II above.
[000151] For example, in one aspect, the disclosure provides a method of selecting a therapy for a subject suffering from MS, the method including: (a) determining in a sample derived from a subject suffering from MS the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., polymorphism rsl0633091 (SEQ ID NO: 6)), wherein the presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rs!0633091 (SEQ ID NO: 6)) indicates that the subject has an increased risk of MS progression; and (b) selecting a therapy including a DMT (e.g., an immunomodulatory DMT) agent for the subject who has been identified as having an increased risk of MS progression. In some embodiments, the subject’s genotype includes a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), such as polymorphism rs!0633091 (SEQ ID NO: 6). In some embodiments, the subject’s genotype includes an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6).
[000152] In another example, the disclosure provides a method of determining whether a subject is at increased risk of MS progression, the method including determining the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., polymorphism rsl0633091 (SEQ ID NO: 6)) in a sample derived from the subject, wherein the subject is at increased risk of MS progression if the genotype of the subject includes a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rs!0633091 (SEQ ID NO: 6)). In some embodiments, the subject’s genotype includes a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), such as polymorphism rsl0633091 (SEQ ID NO: 6). In some embodiments, subject’s genotype includes an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6).
[000153] Tn another example, the disclosure provides a method of selecting a therapy for a subject at risk of developing MS (e.g., an early onset of MS), the method including: (a) determining in a sample derived from a subject the genotype at one or more of (i) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of developing MS; (iii) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iv) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of developing MS; (v) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of developing MS; and/or (vi) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of developing MS; and (b) selecting a therapy including a DMT (e.g., an immunomodulatory DMT) agent for the subject who has been identified as having an increased risk of developing MS (e.g., an early onset of MS). In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the equivalent allele is a C allele at polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
[000154] In another example, the disclosure provides a method of determining whether a subject is at increased risk of developing MS (e.g., and early onset of MS), the method including determining in a sample derived from the subject the genotype at one or more of (a) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the subject is at increased risk of developing MS (e.g., an early onset of MS) if the genotype of the subject includes a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (b) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the subject is at increased risk of developing MS if the genotype of the subject includes a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk of developing MS (e.g., an early onset of MS); (iv) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of developing MS; (v) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of developing MS; and/or (vi) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of developing MS. In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the equivalent allele is a C allele at polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
[000155] In another example, the disclosure provides a method of selecting a therapy for a subject at reduced risk of developing an early onset of MS, the method including: (a) determining in a sample derived from the subject the genotype at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each A allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a reduced risk of developing an early onset of MS; and (b) selecting a therapy including a DMT agent (e.g., an immunomodulatory DMT agent) for the subject who has been identified as having a risk of developing an early onset of MS. [000156] In another example, the disclosure provides a method of determining whether a subject is at reduced risk of developing an early onset of MS, the method including determining the genotype at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) in a sample derived from the subject, wherein the subject is at reduced risk of developing an early onset of MS if the genotype of the subject includes an A allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2).
[000157] In some examples, the presence of an A allele at polymorphism rs3129882 (SEQ ID NO: 2) in a subject’s genome delays AAO by 1 .24 years, e.g., compared to an individual whose genome includes the presence of a G allele at polymorphism rs3129882 (SEQ ID NO: 2).
[000158] In any of the foregoing examples, a therapy (e.g., an immunomodulatory DMT agent) may be administered to the subject using the therapeutic methods described in Section II above.
Subjects
[000159] The present disclosure provides for methods of treating a subject (e.g., a human) with one or more (e.g., 1, 2, 3, 4, 5, 6, or more) of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a C allele at polymorphism rs3092737 (SEQ ID NO: 4); (v) a C allele at polymorphism rs3092258 (SEQ ID NO: 5); (vi) an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6); (vii) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (viii) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (ix) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (x) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (xi) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1); (xii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), (xiii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (xiv) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (xv) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (xvi) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and (xvii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12). It is within the scope of the invention that the subject to be treated by the methods described herein includes any one of the aforementioned genotypes or any combination of the aforementioned genotypes.
[000160] As is demonstrated herein, a subject with a C allele at polymorphism rs4962725 (SEQ ID NO: 1) (also referred to herein as “rs4962725C”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), e.g., an insertion of AG at polymorphism rs 10633091 (SEQ ID NO: 6), is at an increased risk of MS progression (e.g., in terms of rate of T2LVC), compared to a subject whose genotype does not contain a C allele (e.g., a subject containing a T allele) at polymorphism rs4962725 (SEQ ID NO: 1), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1).
[000161] As is also demonstrated herein, a subject with a G allele at polymorphism rs3129882 (SEQ ID NO: 2) (also referred herein as “rs3129882G”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), is at risk of developing MS, such as an early age-at-onset (AAO) of MS, compared to a subject whose genotype does not contain a G allele (e.g., a subject containing an A allele) at polymorphism rs3129882 (SEQ ID NO: 2), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2).
[000162] As is also demonstrated herein, a subject with a G allele at polymorphism rs3091826 (SEQ ID NO: 3) (also referred herein as “rs3091826G”), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5), is at risk of developing MS, such as an early AAO of MS, compared to a subject whose genotype does not contain a G allele (e.g., a subject containing an A or a T allele) at polymorphism rs3091826 (SEQ ID NO: 3), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3).
[000163] As is also demonstrated herein, a subject with a T allele at polymorphism rs28672722 (SEQ ID NO: 9), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), is at risk of developing MS, such as an early AAO of MS, compared to a subject whose genotype does not contain a T allele at polymorphism rs28672722 (SEQ ID NO: 9), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9). [000164] As is also demonstrated herein, a subject with a T allele at polymorphism rs37411 (SEQ ID NO: 10), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), is at risk of developing MS, such as an early AAO of MS, compared to a subject whose genotype does not contain a T allele at polymorphism rs37411 (SEQ ID NO: 10), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10).
[000165] As is also demonstrated herein, a subject with a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), is at risk of developing MS, such as an early AAO of MS, compared to a subject whose genotype does not contain a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11).
[000166] As is also demonstrated herein, a subject with an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or a subject with an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), is at risk of developing MS, such as an early AAO of MS, compared to a subject whose genotype does not contain an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or the equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[000167] In some embodiments, the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)). In some embodiments, the subject has the following genotype: a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882. In some embodiments, the subject has the following genotype: a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)). In some embodiments, the subject has the following genotype: a T allele at polymorphism rs28672722 (SEQ ID NO: 9), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9). In some embodiments, the subject has the following genotype: a T allele at polymorphism rs37411 (SEQ ID NO: 10), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10). In some embodiments, the subject has the following genotype: a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11). In some embodiments, the subject has the following genotype: an A allele at polymorphism rs28359884 (SEQ ID NO: 12), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[000168] In some embodiments, the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl 0633091 (SEQ ID NO: 6)); and a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882.
[000169] In some embodiments, the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5))
[000170] In some embodiments, the subject has the following genotype: a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882; and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)).
[000171] In some embodiments, the subject has the following genotype: a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882; and a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)).
[000172] In some embodiments, the subject has the genotype comprising or consisting of one or more of any of the following: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882; (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722; (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411; (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[000173] In some embodiments, the subject has any one of the following genotypes: a C allele at polymorphism rs4962725 (SEQ ID NO: 1); a G allele at polymorphism rs3129882 (SEQ ID NO: 2); a G allele at polymorphism rs3091826 (SEQ ID NO: 3); a T allele at polymorphism rs28672722 (SEQ ID NO: 9); a T allele at polymorphism rs37411 (SEQ ID NO: 10); a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); an A allele at polymorphism rs28359884 (SEQ ID NO: 12);an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)); an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[000174] In some embodiments, the subject has any two, three, four, five, six, seven, eight, nine, or ten of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6)); (ix) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (x) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); (xi) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (xii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (xiii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (xiv) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[000175] In some embodiments, the subject has all of the following genotypes: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1); (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2); (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3); (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9); (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10); (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12); (viii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (e.g., an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6)); (ix) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2); (x) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (e g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)); (xi) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); (xii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10); (xiii) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or (xiv) an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
[000176] In any of the preceding embodiments, the equivalent allele may be at an alternate single nucleotide polymorphism (SNP) that is in linkage disequilibrium with one or more of the selected SNPs described herein (e.g., rs4962725 (SEQ ID NO: 1); rs3129882 (SEQ ID NO: 2); rs3091826 (SEQ ID NO: 3)); rs28672722 (SEQ ID NO: 9); rs37411 (SEQ ID NO: 10); rsl 1755689 (SEQ ID NO: 11); and/or rs28359884 (SEQ ID NO: 12). Tn some embodiments, the equivalent allele that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1) is an insertion of AG at polymorphism rslO633O91 (SEQ ID NO: 6). In some embodiments, the equivalent allele that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3) is a C allele at polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the equivalent allele that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3) is a C allele at polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the subject’s genotype includes a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
[000177] In some embodiments, the linkage disequilibrium is a D’ value or an r2 value. In some embodiments, the D’ measure between the selected SNP and the alternate SNP is > 0.60 (e.g., > 0.60, > 0.65, > 0.7, > 0.75, > 0.8, > 0.85, > 0.9, > 0.95, or higher). In some embodiments, the D’ value between the selected SNP and the alternate SNP is >0.70, > 0.80, or > 0.90. In some embodiments, the D’ value between the selected SNP and the alternate SNP is 1.0. In some embodiments, the r2 value between the selected SNP and the alternate SNP is > 0.60 (e.g., > 0.60, > 0.65, > 0.7, > 0.75, > 0.8, > 0.85, > 0.9, > 0.95, or higher). In some embodiments the r2 value between the selected SNP and the alternate SNP is > 0.70, > 0.80, or > 0.90. In some embodiments, the r2 value between the selected SNP and the alternate SNP is 1.0. In any of the preceding methods, the equivalent allele may be the minor allele or the major allele. In some instances, the equivalent allele is the minor allele. In other instances, the equivalent allele is the major allele.
[000178] In some embodiments, the genotype of the subject is derived from a sample of the subject, such as blood, plasma, serum, urine, saliva, stool, pleural fluid, lymphatic fluid, sputum, ascites, prostatic fluid, cerebrospinal fluid (CSF), or any other bodily secretion or derivative thereof. In some embodiments, the sample derived from the subject is a whole blood sample, a serum sample, a plasma sample, or a combination thereof. In some embodiments, the sample derived from the subject is a whole blood sample. In some embodiments, the sample derived from a subject is a serum sample. In some embodiments, the sample derived from a subject a plasma sample.
[000179] The genotype of a subject can be determined using any of the methods or assays described herein or that are known in the art.
III. Genotyping
[000180] In several embodiments, the methods of treatment (e.g., as described in Section II above) and/or diagnostic (e.g., as described in Section III above) provided by the invention involve determining of the genotype of a subject at one or more polymorphisms (e.g., SNPs) described herein (e.g., a subject with a C allele at polymorphism rs4962725 (SEQ ID NO: 1); a G allele at polymorphism rs3129882 (SEQ ID NO: 2); a G allele at polymorphism rs3091826 (SEQ ID NO: 3); a T allele at polymorphism rs28672722 (SEQ ID NO: 9); a T allele at polymorphism rs37411 (SEQ ID NO: 10); a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11); an A allele at polymorphism rs28359884 (SEQ ID NO: 12); and/or an equivalent allele at a polymorphism that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1), rs3129882 (SEQ ID NO: 2), rs3091826 (SEQ ID NO: 3), rs28672722 (SEQ ID NO: 9), rs37411 (SEQ ID NO: 10); rsl 1755689 (SEQ ID NO: 11); and/or rs28359884 (SEQ ID NO: 12)).
[000181] Determination of the presence or absence of a particular allele (e.g., a SNP) is generally performed by analyzing a nucleic acid sample that is obtained from the subject to be analyzed. Often, the nucleic acid sample includes genomic DNA. The genomic DNA is typically obtained from blood samples but may also be obtained from other cells or tissues (e.g., hair or skin).
[000182] Any suitable approach for determining a subject’s genotype may be used. Exemplary, non-limiting approaches are summarized below.
[000183] Detection techniques for evaluating nucleic acids for the presence of a SNP involve procedures well known in the field of molecular genetics. Many, but not all, of the methods involve amplification of nucleic acids. Ample guidance for performing amplification is provided in the art. Exemplary references include manuals such as Erlich, ed., PCR Technology: Principles and Applications for DNA Amplification, Freeman Press, 1992; Innis et al. eds., PCR Protocols: A Guide to Methods and Applications, Academic Press, 1990; Ausubel, ed., Current Protocols in Molecular Biology, 1994-1999, including supplemental updates through April 2004; and Sambrook et al. eds., Molecular Cloning, A Laboratory Manual, 2001. General methods for detection of single nucleotide polymorphisms are disclosed in Kwok, ed., Single Nucleotide Polymorphisms: Methods and Protocols, Humana Press, 2003.
[000184] Although the methods typically employ PCR steps, other amplification protocols may also be used. Suitable amplification methods include ligase chain reaction (see, e.g., Wu et al. Genomics 4:560-569, 1988); strand displacement assay (see, e.g., Walker et al. Proc. Natl. Acad. Sci. USA 89:392-396, 1992; U.S. Pat. No. 5,455,166); and several transcription-based amplification systems, including the methods described in U.S. Pat. Nos. 5,437,990; 5,409,818; and 5,399,491; the transcription amplification system (TAS) (Kwoh et al. Proc. Natl. Acad. Sci. USA 86: 1 173-1 177, 1989); and self-sustained sequence replication (3 SR) (Guatelli et al. Proc. Natl. Acad. Sci. USA 87: 1874-1878, 1990; WO 1992/08800). Alternatively, methods that amplify the probe to detectable levels can be used, such as QP-replicase amplification (Kramer et al. Nature 339:401-402, 1989; Lomeli et al. Clin. Chem. 35: 1826-1831, 1989). A review of known amplification methods is provided, for example, by Abramson et al. Curr. Opin. Biotech. 4:41-47, 1993.
[000185] Detection of the genotype, haplotype, SNP, microsatellite, or other polymorphism of a subject can be performed using oligonucleotide primers and/or probes. Oligonucleotides can be prepared by any suitable method, usually chemical synthesis. Oligonucleotides can be synthesized using commercially available reagents and instruments. Alternatively, they can be purchased through commercial sources. Methods of synthesizing oligonucleotides are well known in the art (see, e.g., Narang et al. Meth. Enzymol. 68:90-99, 1979; Brown et al. Meth. Enzymol. 68: 109-151, 1979; Beaucage et al. Tetra. Lett. 22:1859-1862, 1981; and the solid support method of U.S. Pat. No. 4,458,066). In addition, modifications to the above-described methods of synthesis may be used to desirably impact enzyme behavior with respect to the synthesized oligonucleotides. For example, incorporation of modified phosphodiester linkages (e.g., phosphorothioate, methylphosphonates, phosphoamidate, or boranophosphate) or linkages other than a phosphoric acid derivative into an oligonucleotide may be used to prevent cleavage at a selected site. In addition, the use of 2’-amino modified sugars tends to favor displacement over digestion of the oligonucleotide when hybridized to a nucleic acid that is also the template for synthesis of a new nucleic acid strand.
[000186] The genotype of a subject (e.g., a subject suffering from or at risk of developing MS) can be determined using many detection methods that are well known in the art. Most assays entail one of several well-known molecular techniques: hybridization using allele-specific oligonucleotides, primer extension, allele-specific ligation, sequencing, or electrophoretic separation techniques, e.g., single-stranded conformational polymorphism (SSCP) and heteroduplex analysis. Exemplary assays include 5’-nuclease assays, template-directed dye-terminator incorporation, molecular beacon allele-specific oligonucleotide assays, single-base extension assays, and SNP scoring by real-time pyrophosphate sequences. Analysis of amplified sequences can be performed using various technologies such as microchips, fluorescence polarization assays, and MALDI-TOF (matrix assisted laser desorption ionization-time of flight) mass spectrometry. Two methods that can also be used are assays based on invasive cleavage with Flap nucleases and methodologies employing padlock probes.
[000187] In some examples, it is also possible to analyze RNA samples for the presence of polymorphic alleles. For example, mRNA can be used to determine the genotype of a subject at one or more polymorphic sites. In this case, the nucleic acid sample is obtained from cells in which the target nucleic acid is expressed. Such an analysis can be performed by first reverse-transcribing the target RNA using, for example, a viral reverse transcriptase, and then amplifying the resulting cDNA; or using a combined high-temperature reverse-transcription-polymerase chain reaction (RT- PCR), as described in U.S. Pat. Nos. 5,310,652; 5,322,770; 5,561,058, 5,641,864; and 5,693,517.
IV. Kits
[000188] In some embodiments, the invention provides a kit for carrying out the methods of the invention, for example, for determining the genotype of a subject at a polymorphism described herein. In some embodiments, the invention provides a kit for determining whether a subject is at risk of MS progression and/or at risk of developing an early onset of MS.
[000189] A kit of the invention may contain an oligonucleotide (e.g., a probe or primer) capable of specifically hybridizing to one of the following polymorphic alleles: (i) a C allele at polymorphism rs4962725 (SEQ ID NO: 1), (ii) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), (iii) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), (iv) a T allele at polymorphism rs28672722 (SEQ ID NO: 9), (v) a T allele at polymorphism rs37411 (SEQ ID NO: 10), (vi) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), (vii) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), (viii) an equivalent allele at a polymorphism that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1) (e.g., an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)), (ix) an equivalent allele at a polymorphism that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2), (x) an equivalent allele at a polymorphism that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3) (e.g., a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5)), (xi) an equivalent allele at a polymorphism that is in linkage disequilibrium with rs28672722 (SEQ ID NO: 9), (xii) an equivalent allele at a polymorphism that is in linkage disequilibrium with rs37411 (SEQ ID NO: 10); (xiii) an equivalent allele at a polymorphism that is in linkage disequilibrium with rsl 1755689 (SEQ ID NO: 11); and/or (xii) an equivalent allele at a polymorphism that is in linkage disequilibrium with rs28359884 (SEQ ID NO: 12). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a C allele at polymorphism rs4962725 (SEQ ID NO: 1). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a G allele at polymorphism rs3129882 (SEQ ID NO: 2). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a G allele at polymorphism rs3091826 (SEQ ID NO: 3). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a C allele at polymorphism rs3092737 (SEQ ID NO: 4). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a C allele at polymorphism rs3092258 (SEQ ID NO: 5). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an AG allele inserted at polymorphism rsl0633091 (SEQ ID NO: 6). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a T allele at polymorphism rs28672722 (SEQ ID NO: 9). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a T allele at polymorphism rs37411 (SEQ ID NO: 10). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an A allele at polymorphism rs28359884 (SEQ ID NO: 12). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs4962725 (SEQ ID NO: 1). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs3129882 (SEQ ID NO: 2). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs3091826 (SEQ ID NO: 3). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs28672722 (SEQ ID NO: 9). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs37411 (SEQ ID NO: 10). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rsl 1755689 (SEQ ID NO: 11). In some embodiments, the kit contains an oligonucleotide capable of specifically hybridizing to an equivalent allele at a polymorphism that is in linkage disequilibrium with rs28359884 (SEQ ID NO: 12).
[000190] Oligonucleotides “capable of specifically hybridizing” a genetic locus (e.g., a genetic locus that includes a polymorphic allele or SNP) bind either to the polymorphic region of the locus or bind adjacent to the polymorphic region of the locus. For oligonucleotides that are to be used as primers for amplification of a locus containing the polymorphism (e.g., for use in next generation sequencing or Sanger sequencing), primers are adjacent if they are sufficiently close to be used to produce a polynucleotide including the polymorphic region. In one embodiment, oligonucleotides are adjacent if they bind within about 1-2 kb, e.g., less than 1 kb from the polymorphism. Specific oligonucleotides are capable of hybridizing to a sequence, and under suitable conditions will not bind to a sequence differing by a single nucleotide.
[000191] Oligonucleotides, whether used as probes or primers, contained in a kit can be detectably labeled. Labels can be detected either directly, for example for fluorescent labels, or indirectly. Indirect detection can include any detection method known to one of skill in the art, including biotin-avidin interactions, antibody binding and the like. Fluorescently labeled oligonucleotides also can contain a quenching molecule. Oligonucleotides can be bound to a surface. In some embodiments, the surface is silica or glass. In some embodiments, the surface is a metal electrode.
[000192] In some embodiments, the kit may contain one or more reagents (e.g., a buffer, preservative, and/or diluent) necessary to perform hybridization of the oligonucleotide to a subject’s nucleic acid sample. The one or more reagents may be in the form of a liquid or a lyophilized powder and stored within one or more containers.
[000193] The kits may further include a positive control, a negative control, sequencing markers, and/or sequencing primers. Kits may also include instructions for use and for interpreting the results obtained using the kit. V. Definitions
[000194] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art, unless otherwise defined. Any suitable materials and/or methodologies known to those of ordinary skill in the art can be utilized in carrying out the methods described herein.
[000195] The term “administering” means the administration of a pharmaceutical composition (e.g., an immunomodulatory disease-modifying therapeutic (DMT) agent) to a subject (e.g., a subject suffering from multiple sclerosis (MS)).
[000196] The term “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term. For example, in some embodiments, it will mean plus or minus 5% of the particular term. Certain ranges are presented herein with numerical values being preceded by the term "about." The term "about" is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number, which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number.
[000197] As used herein, the term “comprising” is intended to mean that the compounds, compositions and methods include the recited elements, but not exclude others. “Consisting essentially of’ when used to define compounds, compositions and methods, shall mean excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants, e.g., from the isolation and purification method and pharmaceutically acceptable carriers, preservatives, and the like. “Consisting of’ shall mean excluding more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of this technology.
[000198] As used herein, the terms “age-at-onsef ’ or “AAO” refer to the age at which an individual acquires, develops, or first experiences symptoms of a disease or disorder (e.g., MS) or is diagnosed as having a disease or disorder (e.g., MS). Typically, AAO for MS is about 20 to about 40 years of age. Procedures for diagnosing MS may include one or more of the following: blood tests and/or spinal taps (lumbar puncture), e.g., to evaluate biomarkers associated with MS, magnetic resonance imaging (MRI), e.g., to evaluate lesions in the brain and/or spinal cord, evoked potential tests assessing electrical signals produced by the nervous system in response to stimuli (e.g., visual or electrical stimuli), and an oligoclonal band test for screening the cerebrospinal fluid (CSF) for immunoglobulin bands associated with MS.
[000199] The term “alternate SNP” when used herein refers to a SNP that is expected to behave similarly to a selected SNP and is selected based on similar allele frequencies and/or has linkage disequilibrium with a selected SNP as measured by an r2> 0.6 and/or D’ > 0.6. Alternate SNPs include SNPs that are in linkage disequilibrium with the SNPs described herein (e.g., rs4962725 (SEQ ID NO: 1); rs3129882 (SEQ ID NO: 2); and rs3091826 (SEQ ID NO: 3)).
[000200] The term “a subject suffering from” refers to a subject showing clinical signs in respect to a certain disease, for example, any form of MS (e.g., clinically isolated syndrome (CIS), relapsingremitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS), progressive forms of MS (PMS), and relapsing MS (RMS)).
[000201] As used herein, the term “early onset” refers to a disease, disorder, or condition occurring early in a subject’s life, e.g., in relation to other subjects with the disease, disorder, or condition. For example, subjects with a G allele at polymorphism rs3129882 (SEQ ID NO: 2) are more likely to experience an early onset of MS compared to subjects with an A allele at polymorphism rs3129882. In particular, the presence of one copy of an A allele at polymorphism rs3129882 (SEQ ID NO: 2) delays AAO by approximately 1.24 years. In another example, subjects with a G allele at polymorphism rs3091826 (SEQ ID NO: 3) are more likely to experience an early onset of MS compared to subjects with an A or a T allele at polymorphism rs3091826. In particular, the presence of one copy of a G allele reduces the AAO by about 3 years. Additionally, subjects with a C allele at polymorphism rs3092737 (SEQ ID NO: 4) or a C allele at polymorphism rs3092258 (SEQ ID NO: 5) are also more likely to experience an early onset of MS. Additionally, subjects with a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or a T allele at polymorphism rs37411 (SEQ ID NO: 10) were more likely to experience an early onset of MS. Additionally, subjects with a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an A allele at polymorphism rs28359884 (SEQ ID NO: 12) were more likely to experience an early onset of MS. [000202] “Equivalent allele” or “surrogate allele,” as used herein, refers to an allele that is expected to behave similarly to a risk allele and is selected based on allele frequencies and/or high r2 value (greater than or equal to (>) 0.6) and/or high D’ value (>0.6) with the risk alleles and/or selected SNP as defined herein. In one embodiment, the high r2 value is > 0.6, > 0.7, >0.8, >0.9, or 1.0. In one embodiment, the high D’ value is > 0.6, > 0.7, > 0.8, > 0.9, or 1.0.
[000203] The term “effective amount” refers to an amount of a drug effective to treat a disease or disorder (e.g., MS (e.g., CIS, RRMS, PPMS, SPMS, PMS, and RMS)) in a subject or subject, such as a mammal, e.g., a human.
[000204] The term “genotype” refers to a description of the alleles of a gene contained in a subject or a sample. In the context of this invention, no distinction is made between the genotype of a subject and the genotype of a sample originating from the subject. Although typically a genotype is determined from samples of diploid cells, a genotype can be determined from a sample of haploid cells, such as a sperm cell.
[000205] As used herein, the terms “disease modifying therapeutic agent” and “DMT agent” refer to a therapeutic agent that prevents or mitigates the severity of relapse events, the frequency of relapse events, the accumulation of disability, and the accumulation of new lesions in the brain and/or spinal cord in a subject with MS. In some examples, the DMT agent may be an “immunomodulatory DMT agent,” which may confer therapeutic benefit by modulating or suppressing the immune system. Exemplary immunomodulatory DMT agents include: interferon beta (IFNP) agents; monoclonal antibodies (mAbs); sphingosine 1-phosphate receptor modulators; anthracenedione antineoplastics; pyrimidine synthesis inhibitors; polymers of glutamic acid, lysine, alanine, and tyrosine; fumarate agents; and antimetabolites.
[000206] A “kit” is any manufacture (e.g., a package or container) that includes at least one reagent, for example, a probe for determining the genotype of a polymorphism as described herein. The manufacture may be promoted, distributed, or sold as a unit for performing the methods of the present invention.
[000207] “Linkage disequilibrium” or “LD” when used herein refers to alleles at different loci that are not associated at random, i.e., not associated in proportion to their frequencies. If the alleles are in positive linkage disequilibrium, then the alleles occur together more often than expected assuming statistical independence. Conversely, if the alleles are in negative linkage disequilibrium, then the alleles occur together less often than expected assuming statistical independence.
[000208] As used herein, the term “MS progression” refers to a progression or accumulation of T2 hyperintense lesion volume (T2LV) in a subject with MS. MS progression can be observed by standard MRI techniques (e.g., observing an accumulation of lesions in the brain, as observed by MR1, over at least two time points). See the definition of “T2 magnetic resonance imaging lesion volume change” and “T2LVC” for additional context.
[000209] The term "pharmaceutical composition" refers to a sterile preparation that is in such form as to permit the biological activity of the medicament to be effective, and which contains no additional components that are unacceptably toxic to a subject to which the formulation would be administered
[000210] A nucleotide position in a genome at which more than one sequence is possible in a population is referred to herein as a “polymorphism” or “polymorphic site.” A polymorphic site may be a nucleotide sequence of two or more nucleotides, an inserted nucleotide or nucleotide sequence, a deleted nucleotide or nucleotide sequence, or a microsatellite, for example. A polymorphic site that is two or more nucleotides in length may be 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more, 20 or more, 30 or more, 50 or more, 75 or more, 100 or more, 500 or more, or about 1000 nucleotides in length, where all or some of the nucleotide sequences differ within the region. A polymorphic site which is a single nucleotide in length is referred to herein as a single nucleotide polymorphism (SNP), as described below. When there are two, three or four alternative nucleotide sequences at a polymorphic site, each nucleotide sequence is referred to as a “polymorphic variant” or “nucleic acid variant.” Each possible variant in the DNA sequence is referred to as an “allele.” Typically, the first identified allelic form is arbitrarily designated as the reference form and other allelic forms are designated as alternative or variant alleles. A “common” allele is an allele that is prevalent in a given population, e.g., the allele is present in multiple members of a population at a generally accepted frequency of greater than about 2%. Where two polymorphic variants exist, the polymorphic variant represented in a majority of samples from a population is referred to as a “prevalent allele,” or “major allele,” and the polymorphic variant that is less prevalent in the population is referred to as an “uncommon allele” or “minor allele.” A subject who carries two prevalent alleles or two uncommon alleles is “homozygous” with respect to the polymorphism. A subject who carries one prevalent allele and one uncommon allele is “heterozygous” with respect to the polymorphism. With C/G or A/T SNPs, the alleles are ambiguous and dependent on the strand used to extract the data from the genotyping platform. With these C/G or A/T SNPs, the C or G nucleotide or the A or T nucleotide, respectively, may be the risk allele and is determined by correlation of allele frequencies.
[000211] The allele that correlates with an increased risk for a disease or disorder (e.g., MS), increased risk for progression for a disease or disorder (e.g., MS) (e.g., in terms of rate of T2 magnetic resonance imaging lesion volume change (T2LVC)), age at onset for a disease or disorder (e.g., MS), or is associated with an odds ratio or relative risk of >1 may be referred to as the “risk allele” or “effect allele.” The “risk allele” or “effect allele” may be the minor allele or major allele
[000212] The terms “sample” and “biological sample” are used interchangeably to refer to any biological sample obtained from a subject including body fluids, body tissue, nasal samples (including nasal swabs or nasal polyps), sputum, cells, or other sources. Body fluids include, e.g., lymph, sera, whole fresh blood, frozen whole blood, plasma (including fresh or frozen), peripheral blood mononuclear cells, urine, saliva, semen, synovial fluid and spinal fluid. Methods for obtaining tissue biopsies and body fluids from mammals are well known in the art.
[000213] The term “single nucleotide polymorphism” or “SNP” refers to a single base substitution within a DNA sequence that leads to genetic variability. Single nucleotide polymorphisms may occur at any region of a gene. In some instances, the polymorphism can result in a change in protein sequence. The change in protein sequence may affect protein function or not.
[000214] The term “selected SNP” when used herein refers to a SNP selected from the group consisting of polymorphism rs4962725 (SEQ ID NO: 1); rs3129882 (SEQ ID NO: 2); and rs3091826 (SEQ ID NO: 3).
[000215] The term “subject” refers to any single animal, more specifically a mammal (including such non-human animals as, for example, dogs, cats, horses, rabbits, zoo animals, cows, pigs, sheep, and non-human primates) for which diagnosis or treatment is desired. Even more specifically, the subject herein is a human that is diagnosed with any form of MS (e.g., CIS, RRMS, PPMS, SPMS, PMS, and RMS).
[000216] As used herein, the terms “T2 magnetic resonance imaging lesion volume (T2LV) change” and “T2LVC” refer to a progression or accumulation of T2LV in a subject with MS that can be used as a measure of MS progression. T2LVC can be assessed by imaging lesions (e.g., T2LV) in the brain, as observed by MRI, over at least two or more time points. For example, T2LVC may be computed as the percent change in T2LV from the first to the last brain MRI.
[000217] As used herein, “therapy” or “treatment” refers to clinical intervention in an attempt to alter the natural course of the subject or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of a relapse of MS, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
EXAMPLES
[000218] The following examples are provided to illustrate, but not to limit the claimed invention.
[000219] Example 1. Genome-wide study for T2 MRI lesion volume progression rate in multiple sclerosis identifies a novel association in CTBP2
[000220] Introduction
[000221] Studies have identified over 200, largely autoimmune loci associated with multiple sclerosis (MS) risk, validating the immunomodulatory mechanisms of MS therapies. While therapies are effective for suppressing MS disease activity, they are only modestly effective in preventing disability progression, the unmet need. MS PATHS (Partners Advancing Technology and Health Solutions) is a large, multi-center, real world MS cohort with longitudinal clinical, digital, MRI, and biological data. Whole-genome sequencing (WGS) in MS PATHS offers an unprecedented opportunity to interrogate mechanisms driving MS disability progression.
[000222] Methods
[000223] We performed whole genome sequencing (WGS) at 30X in 7,938 MS PATHS subjects followed by data processing and joint genotyping using BWA-GATK. We performed a genomewide association study (GWAS) for age-at-onset (AAO) and for rate of T2LV change (T2LVC), a measure of lesion accumulation on brain MRI, in European Ancestry (EA) subjects. T2LVC was computed as the percent change in T2LV from the first to the last brain MRI. Both phenotypes were rank-based inverse-normal transformed prior to analyses. Novel associations were cross-referenced with known complex trait loci, UK Biobank phenotypes, and cell-specific expression and epigenetic datasets. [000224] Results
[000225] Overall, 114.5 million variants were called across 7,938 subjects. Genome-wide test inflation was not detected (AAO: =1.011 ; T2VC: X=1.009). The AAO analysis (N=6,210) replicated a known association with DRBl*15:01 (rs3135388A, P=3.0e-6), the top MS risk allele, and identified two novel associations: an intronic SNV in HLA-DRA (rs3129882A, (3=0.113, s.e =0.018, P=2.6e-10) and an intronic SNV in EYA2 (rs3091826G, £=-0.279 s.e =0.05, P=2.7e-8).
[000226] The rs3091826G allele in ETA? was associated with an increased risk of developing an early AAO for MS; subjects with one copy of the rs3091826G allele experienced onset of MS about 3 year earlier than subjects with the rs3091826A or rs3091826T allele. Two equivalent alleles (i.e., surrogate alleles) in linkage disequilibrium with polymorphism rs3091826G were also identified: a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and a C allele at polymorphism rs3092258 (SEQ ID NO: 5). The EYA2 locus harbors known associations with waist-to-hip ratio (rsl 1698093).
[000227] Conversely, the rs3129882A allele in HLA-DRA was associated with a decreased risk of developing an early AAO for MS; subjects with one copy of the rs3129882A allele experienced onset of MS about 1.24 years later than subjects with the rs3129882G allele.
[000228] The T2LVC analysis (N=2,657; median 2.6 years between brain MRIs) identified a novel association in an intron of CTBP2 (rs4962725C, £=0.158, s.e =0.027, P=7.8e-9) that shows chromatin interaction with the promoter of CTBP2, is also co-localized with a reported association with BMI (probability=0.98). The CTBP2 locus harbors known super-enhancers for oligodendrocytes and astrocytes, and known associations with brain cortical thickness and surface area (rs 1915146). One equivalent allele (i.e., surrogate allele) was identified to be in linkage disequilibrium with polymorphism rs4962725C: an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6), herein referred as “rslO633O91CAG”. In other words, the rsl0633091CAG allele is an insertion of AG nucleotides following the C nucleotide located at chromosome (chr) 10, nucleotide position 125044448 (i.e., chrlO: 125044448), e.g., relative to Genome Reference Consortium Human Build 38 patch release 13 (GRCh38.pl3).
[000229] Discussion
[000230] To our knowledge, this is the largest WGS-based GWAS of AAO and T2VC in MS. We report novel findings implicating the role of HLA and genetic loci associated with BMI, a known MS risk factor, with earlier disease onset. Our data also highlight the potential role of CTBP2, which impacts glial mechanisms, in MS lesion burden accumulation. These findings highlight mechanisms driving MS pathobiology including disability progression.
[000231] Example 2. Adaptive and innate immunity are key drivers of age at onset of multiple sclerosis
[000232] Introduction
[000233] Multiple Sclerosis (MS) age at onset (AAO) is an objective and influential predictor of the evolution of MS independent of disease duration; earlier AAO is associated with greater frequency of relapse during the relapsing-remitting (RR) stage of MS, whereas a later AAO is associated with reaching disability milestones and transitioning to the secondary progressive (SP) stage sooner than individuals with earlier-onset MS. There are few established risk factors for earlier AAO. Females tend to have an earlier AAO, and there is a strong genetic correlation within families. MS risk variant HLA-DRB 1*15:01 has been shown to confer earlier AAO, and an increasing load of MS genetic risk variants have also been associated with an earlier AAO. Few genome-wide association (GW A) analyses have been conducted to investigate direct genetic associations with MS AAO. Existing studies have largely been limited to candidate studies and modestly-powered association analyses, showing little genetic association with MS outside of the major histocompatibility complex (MHC).
[000234] Methods
[000235] The present study provides updated insights into the mechanisms driving early presentation of MS using a well-powered genome-wide association study (GWAS) of AAO in 3,905 persons with MS (PwMS). The study population consisted of unrelated, non-Latinx White PwMS with an AAO >18 years, who were participants in three Group A clinical trials: ADVANCE (N=690), ASCEND (N=582), and DECIDE (N=l,076); and three Group B clinical trials: OPERA1 (N=528), OPERA2 (N=529), and ORATORIO (N=500) see Table 2).
Table 2. Study Population Demographics
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000084_0001
[000236] Genome-wide association analyses were conducted in each trial for AAO (rank- normalized) using linear additive models adjusting for age at enrollment, sex, and ten principal components. Fixed-effects meta-analysis was used to meta-analyze the resulting summary statistics across the six cohorts. Gene-based tests of association were performed using MAGMA vl.06 (de Leeuw et al., PLoS Comput. Biol., //(4):e l 004219 (2015)) in FUMA. Pathway enrichment was evaluated in gene-level associations of p<0.01 using Enrichr (Kuleshov et al., Nucleic Acids Res. 44(Wl):W90-7 (2016); Chen et al., BMC Bioinformatics, 14:128 (2013)). 2-Sample Mendelian randomization (2SMR) analysis was performed to investigate the role of MS risk factors on AAO (body-mass index, vitamin D levels, age at puberty) and telomere length. The multi-step analysis is described in Fig. 1
[000237] Pathway enrichment analyses were completed for three gene sets. The first gene set (GS1) consisted of unique genes in which genic SNPs (as defined by MAGMA) had an AAO association p-value <0.0001; genic SNPs were defined using exact gene boundaries (no flanking regions). SNP annotation was performed using SeattleSeq. The second gene set (GS2) consisted of genes associated with AAO with p-value <0.01 from the gene-based association tests. Lastly, the union of GS1 and GS2 comprised the third gene set (GS3). Pathway enrichment analysis was performed in Enrichr, utilizing the Reactome 2022 database, the KEGG 2021 Human database, and the Human Molecular Signatures Database Hallmark 2020 collection to characterize pathways and diseases enriched in gene sets one through three. Enrichr creates an odds ratio for each enriched pathway from the z-score of the standard deviation of the expected rank, as calculated by a Fisher Exact Test for many random gene sets in the gene-set library. A corresponding p-value is produced from the Fisher Exact Test and taken the natural logarithm of, which is then multiplied by the z-score to calculate the “Combined Score”.
[000238] Results
[000239] After applying QC criteria and filtering for heterogeneity, there were 8.3 x 106 variants. HLA-DRBl*15:01 (tagging SNP rs3135388A) was associated with an earlier AAO (p = 6x l0"4, = -0.09). Four loci were genome-wide significant for MS AAO at a level of p < 5.0x 10" 8. The first locus spanned 43.5 kb within the major histocompatibility complex (MHC) and including three independent signals (r2<0.30) that were not in LD with HLA-DRB1*15:O1 (r2<0.08). Rs28672722T (<1 kb downstream HLA-DQBP, 15 kb downstream HLA-DQA1) was associated with a later AAO of MS (0=0.166, p=l. l Ix lO'9), as were rsl 1755689G (19 kb upstream HLA-DQA 1) and rs28359884A (21 kb upstream HLADQA1 (Table 3; Fig. 2A). These variants were in perfect LD with expression quantitative trait loci (eQTLs) for several HLA and non-HLA genes across multiple tissues, including HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPB1, BRD2, N0TCH4, PRRT1, and C4A, and others (p<5.0*10‘8).
[000240] The second locus was on chromosome 7p21.2, with rs3741 IT, a long noncoding RNA (IncRNA; ENSG00000286376) intronic variant, associated with an earlier AAO of MS (0= -0.253, p=3.64* 10'8) (Table 3; Fig. 2A). This variant is associated with expression of ME0X2 and AGMO (p<0.05). Other non-MHC loci with suggestive independent associations (p<1.0>< 10'5) include an intergenic variant on chromosome 7p 15.3, rs6461685T, that is associated with the expression of adjacent genes: KLHL7, KLPIL7-DT, NUPL2, and GPNMB, and rsl44445292A, and intronic HHIPL1 variant on 14q32.2.
[000241] rs28672722 is a genic SNP located in HLA-DQB1- AS1; it is not in high linkage disequilibrium (LD) with HL A-DRB 1 * 15 (D -0.62, R2=0.02), but it is in perfect LD with rs34438062, which is an eQTL for multiple HLA Class II genes, including HLADRB1.
Figure imgf000085_0001
[000242] The top hit was HLA-C (p= 1.23x 1 O'7), an MHC class I heavy chain paralogue with roles in antiviral immunity. (Table 4; Fig. 3). At the gene-level, HLA-DRB1 was associated with AAO (p=5xl0'3) and the most significant associations (p=5xl0‘5) were for MHC genes HLA-C, HLA- DQA1, and PSORS1C2, and non-MHC genes KLHL7, PLEK and METTL5. Of note, KLHL7 has been associated with risk of Parkinson’s Disease.
Figure imgf000085_0002
Figure imgf000086_0001
[000243] Pathways involved in both adaptive and innate immunity were enriched amongst AAO-associated genes, including multiple cell signaling pathways (p<0.05) and activation of various complement processes (p<0.05) (Table 5).
Figure imgf000086_0002
[000244] GS1, GS2, and GS3 consisted of 157, 319, and 438 genes, respectively. As anticipated, there was an enrichment of pathways involving HLA genes across gene sets (Table 6). For example, in GS3, several of the most significant pathways that included HLA genes were related to T cell receptor signaling, including REACTOME: PD-1 Signaling (p=7.50xl0‘5) and REACTOME: Translocation ofZAP-70 to Immunological Synapse (p=4.31 * 10'4 ); autoimmunity, including KEGG: Type 1 Diabetes Mellitus (p=2.30>< 10'8); and interferon gamma signaling, including REACTOME: Interferon Gamma Signaling (p=7.45x1 O'4) and MSigDB: Interferon Gamma Response (p=0.033). Across databases, there was also an enrichment of complement cascade and other immune signaling pathways including REACTOME: Activation of C3 and C5 (p=l ,99x 10'4), KEGG: Complement and coagulation cascades (p=0.011), MSigDB: Complement (p=0.013), and MSigDB: TNF-alpha Signaling via NK-KB (p=0.033). There were also several non-immune response pathways with high combined scores, such as REACTOME: Gap Junction Assembly (p=0.0047), KEGG: Non-homologous end-joining (p=0.03), and MSigDB: Coagulation (p=2.33x 10' 4). Table 6. Pathway Enrichment Analysis Results for GS3
Figure imgf000087_0001
1. Genes: the list genes submitted to Enrichr which overlapped with the enriched biological pathway.
2. Overlap: the fraction of genes submitted to Enricherthat overlapped with the enriched biological pathway over the total number of genes involved in the enriched biological pathway.
3. Odds ratio: the ratio describing the proportion of genes assigned to a given pathway as compared to the number expected by chance alone.
4. Combined score: calculated by multiplying the natural log of the Fisher Exact Test p-value and the z-score for the expected rank.
5. P-values of the Fisher Exact Test for gene set 1 (GS1 ; genes containing one or genic SNPs as annotated in SeattleSeq), gene set 2 (GS2; genes enriched for MS AAO using MAGMA gene-based tests of association), and gene set 3 (GS3; the union of gene sets 1 and 2).
[000245] 2-Sample MR analyses demonstrated associations between age at puberty and telomere length and MS AAO, respectively (p<0.05), with increases in both exposures being positively associated with AAO. However, no associations were observed for body-mass index or vitamin D levels (Table 7).
Figure imgf000088_0002
Figure imgf000088_0001
[000246] Discussion
[000247] The results of the genome-wide association analysis and subsequent gene and pathway enrichment tests suggest a prominent role for both adaptive and innate immunity in the age of MS onset, particularly the MHC, and specifically the HLA Class II genes and complement activation pathways. Mendelian randomization suggests that there are associations between telomere length and MS AAO, and age at puberty and MS AAO; however, as both of these are age-related traits, further investigation is required to fully understand these associations.
[000248] Other Embodiments
[000249] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

Claims

WHAT IS CLAIMED IS:
1. A method of treating a subj ect suffering from multiple sclerosis (MS), the method comprising administering to the subject a therapy comprising an immunomodulatory diseasemodifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of
(a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1);
(b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2);
(c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3);
(d) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); and/or
(e) a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10);
(f) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or
(g) an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
2. A method of treating a subject suffering from multiple sclerosis (MS), the method comprising:
(a) determining in a sample derived from a subject suffering from MS the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression, and/or (b) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject who has been identified as having an increased risk of MS progression.
3. A method of treating a subject having an increased risk of MS progression, the method comprising administering to the subject a therapy comprising an immunomodulatory diseasemodifying therapeutic agent, wherein the genotype of the subject has been determined to comprise a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), indicating that the subject is at increased risk for MS progression.
4. A method of determining whether a subject is at increased risk of MS progression, the method comprising determining the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) in a sample derived from the subject, wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1).
5. The method of 4, further comprising administering an immunomodulatory diseasemodifying therapeutic agent to the subject.
6. The method of any one of claims 2-5, wherein risk of MS progression is in terms of rate of T2 magnetic resonance imaging lesion volume change (T2LVC).
7. The method of any one of claims 1-6, wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), compared to a subject whose genotype does not comprise a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1).
8. A method of preventing and/or reducing the likelihood of developing MS in a subject, the method comprising administering to the subject a therapy comprising an immunomodulatory disease-modifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of:
(a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1);
(b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2);
(c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3);
(d) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9);
(e) a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10);
(f) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or
(g) an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
9. A method of preventing and/or reducing the likelihood of developing MS in a subject, the method comprising:
(a) determining in a sample derived from the subject the genotype at one or more of:
(i) polymorphism rs3129882 (SEQ ID NO: 2), or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS;
(ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of early onset of MS;
(iii) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk of early onset of MS; and/or
(iv) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of early onset of MS;
(v) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of early onset of MS; and/or
(vi) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of early onset of MS; and
(b) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject who has been identified as having a risk of developing an early onset of MS.
10. A method of treating a subject having an increased risk of early onset of MS, the method comprising administering to the subject a therapy comprising an immunomodulatory diseasemodifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of:
(a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2);
(b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3);
(c) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9);
(d) a T allele at polymorphism rs37411 (SEQ ID NO: 10), or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10);
(e) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or
(f) an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
11. A method of treating a subject having an increased risk of MS progression and/or early onset of MS, the method comprising administering to the subject a therapy comprising an immunomodulatory disease-modifying therapeutic agent, wherein the genotype of the subject has been determined to comprise one or more of:
(a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), indicating that the subject is at increased risk for MS progression;
(b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), indicating that the subject is at increased risk for early onset of MS;
(b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), indicating that the subject is at increased risk for early onset of MS;
(c) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), indicating that the subject is at increased risk for early onset of MS; (d) a T allele at polymorphism rs37411 (SEQ ID NO: 10), or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), indicating that the subject is at increased risk for early onset of MS;
(e) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), indicating that the subject is at increased risk for early onset of MS; and/or
(f) an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), indicating that the subject is at increased risk for early onset of MS.
12. A method of monitoring and/or treating a subject having a risk of developing an early onset of MS, the method comprising:
(a) determining in a sample derived from the subject the genotype at one or more of:
(i) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS;
(ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has a risk of developing an early onset of MS;
(iii) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has a risk of developing an early onset of MS; and/or
(iv) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has a risk of developing an early onset of MS
(v) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 1 1) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has a risk of developing an early onset of MS; and/or
(vi) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has a risk of developing an early onset of MS;
(b) monitoring the subject identified as having a risk of developing an early onset of MS for one or more symptoms of MS;
(c) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and
(d) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject diagnosed with MS.
13. A method of determining whether a subject is at risk of developing an early onset of MS, the method comprising determining in a sample derived from the subject the genotype at one or more of:
(a) polymorphism rs3129882 (SEQ ID NO: 2), wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2);
(b) polymorphism rs3091826 (SEQ ID NO: 3), wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs309I826 (SEQ ID NO: 3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3); (c) polymorphism rs28672722 (SEQ ID NO: 9), wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9);
(d) polymorphism rs37411 (SEQ ID NO: 10), wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10);
(e) polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or
(f) polymorphism rs28359884 (SEQ ID NO: 12) wherein the subject is at risk of developing an early onset of MS if the genotype of the subject comprises an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
14. The method of claim 13, further comprising:
(a) monitoring the subject who has been identified as having a risk of developing an early onset of MS for one or more symptoms of MS;
(b) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and
(c) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject diagnosed with MS.
15. A method of selecting a therapy for a subject suffering from MS, the method comprising:
(a) determining in a sample derived from a subject suffering from MS the genotype at one or more of:
(i) polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression; and/or
(ii) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of early onset of MS;
(iii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs309I826 (SEQ ID NO: 3) indicates that the subject has an increased risk of early onset of MS;
(iv) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk of early onset of MS;
(v) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of early onset of MS
(vi) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of early onset of MS; and/or
(vii) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of early onset of MS; and
(b) selecting a therapy comprising an immunomodulatory disease-modifying therapeutic agent for the subject who has been identified as having an increased risk of MS progression and/or early onset of MS.
16. A method of selecting a therapy for preventing or reducing the likelihood of developing MS in a subject, the method comprising:
(a) determining in a sample derived from a subject the genotype at one or more of:
(i) polymorphism rs3129882 (SEQ ID NO: 2), or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS;
(ii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of early onset of MS;
(iii) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk of early onset of MS; and/or
(iv) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of early onset of MS;
(v) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of early onset of MS
(vi) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of early onset of MS; and
(b) selecting a therapy comprising an immunomodulatory disease-modifying therapeutic agent for the subject who has been identified as having a risk of developing an early onset of MS.
17. A method of selecting a therapy for a subject at risk of developing an early onset of MS, the method comprising:
(a) determining in a sample derived from the subject the genotype at one or more of:
(i) polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), indicates that the subject has a risk of developing an early onset of MS;
(ii) polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), indicates that the subject has a risk of developing an early onset of MS;
(iii) polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), indicates that the subject has a risk of developing an early onset of MS; and/or
(iv) polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), indicates that the subject has a risk of developing an early onset of MS; (v) polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), indicates that the subject has a risk of developing an early onset of MS
(vi) polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12), or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), indicates that the subject has a risk of developing an early onset of MS; and
(b) selecting a therapy comprising an immunomodulatory disease-modifying therapeutic agent for the subject who has been identified as having a risk of developing an early onset of MS.
18. The method of any one of claims 1-17, wherein the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) is polymorphism rsl0633091 (SEQ ID NO: 6), and the equivalent allele is an insertion of AG at polymorphism rsl0633091 (SEQ ID NO: 6)
19. The method of any one of claims 1-18, wherein the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) is polymorphism rs3092737 (SEQ ID NO: 4) and/or polymorphism rs3092258 (SEQ ID NO: 5), and the equivalent allele is a C allele at polymorphism rs3092737 (SEQ ID NO: 4) and/or a C allele at polymorphism rs3092258 (SEQ ID NO: 5).
20. The method of any one of claims 1-19, wherein the subject’s genotype is determined from a sample derived from the subject selected from a whole blood sample, a serum sample, a plasma sample, or a combination thereof.
21. The method of claim 20, wherein the sample derived from the subject is a whole blood sample.
22. The method of any one of claims 1-21, wherein the immunomodulatory diseasemodifying therapeutic agent is selected from the group consisting of an interferon beta (IFNp) agent; a monoclonal antibody (mAb); a sphingosine 1 -phosphate receptor modulator; an anthracenedione antineoplastic; a pyrimidine synthesis inhibitor; a polymer of glutamic acid, lysine, alanine, and tyrosine; a fumarate agent; and an antimetabolite.
23. The method of claim 22, wherein the IFNP agent is selected from AVONEX® (interferon beta-la), BETASERON® (interferon beta-lb), EXTAVIA® (interferon beta-lb), PLEGRIDY® (peginterferon beta-la), and REBIF® (interferon beta-la).
24. The method of claim 22, wherein the mAb is selected from KESIMPTA® (ofatumumab), LEMTRADA® (alemtuzumab), OCREVUS® (ocrelizumab), and TYSABRI® (natalizumab).
25. The method of claim 22, wherein the sphingosine 1-phosphate receptor modulator is selected from GILENYA® (fingolimod), MAYZENT® (siponimod),
PONVORY™ (ponesimod), and ZEPOSIA® (ozanimod).
26. The method of claim 22, wherein the anthracenedione antineoplastic is NOVANTRONE® (mitoxantrone).
27. The method of claim 22, wherein the pyrimidine synthesis inhibitor is AUBAGIO® (teriflunomide).
28. The method of claim 22, wherein the polymer of glutamic acid, lysine, alanine, and tyrosine is selected from COPAXONE® (glatiramer acetate), GLATOPA® (glatiramer acetate), and Glatiramer Acetate Injection (glatiramer acetate).
29. The method of claim 22, wherein the fumarate agent is BAFIERTAM™ (monomethyl fumarate), Dimethyl Fumarate (dimethyl fumarate), TECFIDERA® (dimethyl fumarate), and VUMERITY® (diroximel fumarate).
30. The method of claim 22, wherein the antimetabolite is MAVENCLAD® (cladribine).
31. The method of any one of claims 1, 2, 5-14, and 17-30, further comprising administering an additional therapeutic agent to the subject.
32. The method of claim 31, wherein the additional therapeutic agent is a corticosteroid.
33. The method of claim 31, wherein the additional therapeutic agent is selected from SOLU- MEDROL® (methylprednisolone) or DELTASONE® (prednisone).
34. The method of claim 31, wherein the additional therapeutic agent is a symptom managing agent for treatment of one or more symptoms of MS.
35. The method of claim 34, wherein the symptom is a dysfunctional bladder and the symptom managing agent is selected from BOTOX® (onabotulinumtoxin A), DDAVP Nasal Spray (desmopressin), DETROL® (tolterodine), DITROPAN® (oxybutynin), DITROPAN XL®, ENABLEX® (darifenacin), FLOMAX® (tamsulosin), Prazosin, MYRBETRIQ® (mirabegron), OXYTROL® (oxybutynin), TOFRANIL (imipramine), and VESICARE (solifenacin succinate).
36. The method of claim 34, wherein the symptom is a bladder infection and the symptom managing agent is selected from BACTRIM®, SEPTRA® (sulfamethoxazole),
CIPO® (ciprofloxacin), LEVAQUIN® (levofloxacin), MACRODANTIM® (nitrofurantoin), HIPREX® (methenamine), and PYRIDIUM® (phenazopyridine).
37. The method of claim 34, wherein the symptom is a bowel dysfunction and the symptom managing agent is selected from COLACE® (docusate), DULCOLAX® (bisacodyl), ENEMEEZ® (docusate stool softener laxative), FLEET ENEMA® (sodium phosphate), a mineral oil, METAMUCIL® (psyllium hydrophilic musilloid), Phillips® Milk of Magnesia (magnesium hydroxide), and Sani-Supp® suppository (glycerin).
38. The method of claim 34, wherein the symptom is depression and the symptom managing agent is an antidepressant.
39. The method of claim 38, wherein the antidepressant is selected from a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNR1), a tricyclic antidepressant (TCA), a norepinephrine dopamine reuptake inhibitor (NDRI), a serotonin partial agonist and reuptake inhibitor (SPARI), a serotonin antagonist and reuptake inhibitor (SARI), a monoamine oxidase inhibitor (MAOI), a N-methyl-d-aspartic acid (NMD A) antagonist, and noradrenergic and specific serotonergic antidepressant (NAS SA).
40. The method of claim 38 or 39, wherein the antidepressant is selected from CELEXA® (citalopram), CYMBALTA® (duloxetine hydrochloride), EFFEXOR® (velafaxine), PAXIL® (paroxetine), PROZAC® (fluoxetine), WELLBUTRIN® (bupropion), and ZOLOFT® (sertraline).
41. The method of claim 34, wherein the symptom is dizziness and/or vertigo and the symptom managing agent is ANTIVERT® (meclizine).
42. The method of claim 34, wherein the symptom is pseudobulbar affect and the symptom managing agent is NUEDEXTA® (dextromethorphan and quinidine).
43. The method of claim 34, wherein the symptom is fatigue and the symptom managing agent is selected from ADDERALL® (dextroamphetamine and amphetamine), amantadine, PRO VIGIL® (modafinil), PROZAC® (fluoxetine), and RITALIN® (methylphenidate).
44. The method of claim 34, wherein the symptom is itching and the symptom managing agent is VISTARIL® (hydroxyzine).
45. The method of claim 34, wherein the symptom is pain and the symptom managing agent is selected from CYMBALTA® (duloxetine), EFFEXOR® (venlafaxine), ELAVIL® (amitriptyline), LAMICTAL® (lamotrigine), LYRICA® (pregabalin), NEURONTIN® (gabapentin), PAMELOR® (nortriptyline HCL), AVENTYL® (nortriptyline), TEGETRO®L (carbamazepine), and TR1LEPTAL® (oxcarbazepine).
46. The method of claim 34, wherein the symptom is a sexual problem and the symptom managing agent is selected from CTALTS® (tadalafd), LEVITRA (vardenafil),
MUSE® (alprostadil), PROSTIN VR® (alprostadil), STENDRA® (avanafil), and VIAGRA® (sildenafil).
47. The method of claim 34, wherein the symptom is spasticity and the symptom managing agent is selected from baclofen, BOTOX® (onabotulinumtoxin A), DANTRIUM® (dantrolene), KLONOPIN® (clonazepam), VALIUM® (diazepam), and ZANAFLEX® (tizanidine).
48. The method of claim 34, wherein the symptom is a tremor and the symptom managing agent is selected from LANIAZID® (isoniazid) and KLONOPIN® (clonazepam).
49. The method of claim 34, wherein the symptom is difficulty walking and the symptom managing agent is AMPYRA® (dalfampridine).
50. The method of any one of claims 1-49, wherein the MS is a clinically isolated syndrome (CIS).
51. The method of any one of claims 1-49, wherein the MS is a relapsing-remitting MS (RRMS).
52. The method of any one of claims 1-49, wherein the MS is a primary progressive MS (PPMS).
53. The method of any one of claims 1-49, wherein the MS is a secondary progressive MS (SPMS).
54. An immunomodulatory disease-modifying therapeutic agent for use in treating a subject suffering from MS, wherein the genotype of the subject has been determined to comprise one or more of:
(a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1);
(b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2);
(c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3);
(d) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9); and/or
(e) a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10);
(f) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or
(g) an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
55. The immunomodulatory disease-modifying therapeutic agent for use of claim 54, wherein:
(a) the presence of a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression;
(b) the presence of a G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of developing an early onset of MS;
(c) the presence of a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of developing an early onset of MS;
(d) the presence of a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk an early onset of MS;
(e) the presence of a T allele at polymorphism rs3741 1 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk an early onset of MS;
(f) the presence of a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk an early onset of MS; and/or
(g) the presence of an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk an early onset of MS.
56. An immunomodulatory disease-modifying therapeutic agent for use in a method of treating a subject suffering from MS, the method comprising:
(a) determining in a sample derived from a subject suffering from MS the genotype at:
(i) polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), wherein the presence of each C allele at polymorphism rs4962725 (SEQ ID NO: 1) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) indicates that the subject has an increased risk of MS progression;
(ii) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has an increased risk of developing an early onset of MS;
(iii) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of each G allele at polymorphism rs3091826 (SEQ ID NO: 3) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has an increased risk of an early onset of MS;
(iv) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of each T allele at polymorphism rs28672722 (SEQ ID NO: 9) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) indicates that the subject has an increased risk an early onset of MS;
(v) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of each T allele at polymorphism rs37411 (SEQ ID NO: 10) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) indicates that the subject has an increased risk of an early onset of MS;
(vi) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of each G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has an increased risk of an early onset of MS; and/or
(vii) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of each A allele at polymorphism rs28359884 (SEQ ID NO: 12) or each equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has an increased risk of an early onset of MS; and
(b) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject who has been identified as having an increased risk of MS progression and/or an increased risk of early onset of MS.
57. An immunomodulatory disease-modifying therapeutic agent for use in treating a subject who has who has been previously diagnosed with MS and who has been previously determined to comprise one or more of:
(a) a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1), thereby indicating that the subject has an increased risk of MS progression;
(b) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), thereby identifying the subject as having a risk of developing an early onset of MS;
(c) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), thereby identifying the subject as having a risk of developing an early onset of MS;
(d) a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), thereby indicating that the subject has an increased risk of MS progression; and/or
(e) a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), indicating that the subject has an increased risk of MS progression;
(f) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), indicating that the subject has an increased risk of MS progression; and/or
(g) an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), indicating that the subject has an increased risk of MS progression.
58. An immunomodulatory disease-modifying therapeutic agent for use in preventing and/or reducing the likelihood of developing MS in a subject who has been previously determined to comprise one or more of:
(a) a G allele at polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), thereby identifying the subject as having a risk of developing an early onset of MS; and/or
(b) a G allele at polymorphism rs3091826 (SEQ ID NO: 3), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), thereby identifying the subject as having a risk of developing an early onset of MS; and/or
(c) a T allele at polymorphism rs28672722 (SEQ ID NO: 9), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), thereby identifying the subject as having a risk of developing an early onset of MS;
(d) a T allele at polymorphism rs37411 (SEQ ID NO: 10), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), thereby identifying the subject as having a risk of developing an early onset of MS;
(e) a G allele at polymorphism rsl 1755689 (SEQ ID NO: 1 1), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), thereby identifying the subject as having a risk of developing an early onset of MS; and/or
(f) an A allele at polymorphism rs28359884 (SEQ ID NO: 12), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), thereby identifying the subject as having a risk of developing an early onset of MS.
59. An immunomodulatory disease-modifying therapeutic agent for use in a method of monitoring and treating a subject having a risk of developing an early onset of MS, the method comprising:
(a) determining in a sample derived from the subject the genotype at one or more of:
(i) polymorphism rs3129882 (SEQ ID NO: 2), or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2), wherein the presence of each G allele at polymorphism rs3129882 (SEQ ID NO: 2) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) indicates that the subject has a risk of developing an early onset of MS;
(ii) polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3), wherein the presence of a G allele at polymorphism rs3091826 (SEQ ID NO: 3) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) indicates that the subject has a risk of developing an early onset of MS;
(iii) polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9), wherein the presence of a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9)indicates that the subject has a risk of developing an early onset of MS; (iv) polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10), wherein the presence of a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10)indicates that the subject has a risk of developing an early onset of MS;
(v) polymorphism rsl 1755689 (SEQ ID NO: 1 1) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11), wherein the presence of a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) indicates that the subject has a risk of developing an early onset of MS; and/or
(vi) polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12), wherein the presence of an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) indicates that the subject has a risk of developing an early onset of MS;
(b) monitoring the subject identified as having a risk of developing an early onset of MS for one or more symptoms of MS;
(c) diagnosing the subject with MS when the subject exhibits one or more symptoms of MS; and
(d) administering a therapy comprising an immunomodulatory disease-modifying therapeutic agent to the subject diagnosed with MS.
60. A kit for determining whether a subject is at increased risk of MS progression, the kit comprising one or more reagents for determining the genotype at polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) in a sample derived from a subject, and instructions for use, wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1).
61. A kit for determining whether a subject is at a risk of developing an early onset of MS, the kit comprising one or more reagents for determining the genotype at one or more of:
(a) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3129882 (SEQ ID NO:
2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2);
(b) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3091826 (SEQ ID NO:
3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3);
(c) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at the polymorphism in linkage disequilibrium with rs28672722 (SEQ ID NO: 9);
(d) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10);
(e) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or
(f) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12)) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
62. A kit for determining whether a subject is at increased risk of MS progression and/or whether a subject is at a risk of developing an early onset of MS, the kit comprising one or more reagents for determining the genotype at one or more of:
(a) polymorphism rs4962725 (SEQ ID NO: 1) or at a polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1) in a sample derived from a subject, and instructions for use, wherein the subject is at increased risk of MS progression if the genotype of the subject comprises a C allele at polymorphism rs4962725 (SEQ ID NO: 1) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs4962725 (SEQ ID NO: 1);
(b) polymorphism rs3129882 (SEQ ID NO: 2) or at a polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3129882 (SEQ ID NO:
2) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3129882 (SEQ ID NO: 2);
(c) polymorphism rs3091826 (SEQ ID NO: 3) or at a polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rs3091826 (SEQ ID NO:
3) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs3091826 (SEQ ID NO: 3);
(d) polymorphism rs28672722 (SEQ ID NO: 9) or at a polymorphism in linkage disequilibrium with polymorphism rs28672722 (SEQ ID NO: 9) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs28672722 (SEQ ID NO: 9) or an equivalent allele at the polymorphism in linkage disequilibrium with rs28672722 (SEQ ID NO: 9); and/or
(e) polymorphism rs37411 (SEQ ID NO: 10) or at a polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a T allele at polymorphism rs37411 (SEQ ID NO: 10) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs37411 (SEQ ID NO: 10);
(f) polymorphism rsl 1755689 (SEQ ID NO: 11) or at a polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises a G allele at polymorphism rsl 1755689 (SEQ ID NO: 11) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rsl 1755689 (SEQ ID NO: 11); and/or
(g) polymorphism rs28359884 (SEQ ID NO: 12) or at a polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12) in a sample derived from a subject, and instructions for use, wherein the subject is at a risk of developing an early onset of MS if the genotype of the subject comprises an A allele at polymorphism rs28359884 (SEQ ID NO: 12) or an equivalent allele at the polymorphism in linkage disequilibrium with polymorphism rs28359884 (SEQ ID NO: 12).
I l l
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