WO2019210203A1 - Compositions et procédés de ciblage de gpr35 pour le traitement d'une affection abdominale inflammatoire - Google Patents

Compositions et procédés de ciblage de gpr35 pour le traitement d'une affection abdominale inflammatoire Download PDF

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WO2019210203A1
WO2019210203A1 PCT/US2019/029398 US2019029398W WO2019210203A1 WO 2019210203 A1 WO2019210203 A1 WO 2019210203A1 US 2019029398 W US2019029398 W US 2019029398W WO 2019210203 A1 WO2019210203 A1 WO 2019210203A1
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alkyl
allele
gpr35
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subject
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PCT/US2019/029398
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Dermot P. Mcgovern
Janine Bilsborough
Stephan Targan
Manreet KAUR
Alka POTDAR
Robert Higuchi
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Cedars-Sinai Medical Center
Precision Ibd, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • 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

  • IBD inflammatory bowel disease
  • CD Crohn’s disease
  • UC ulcerative colitis
  • G Protein-Coupled Receptor 35 is linked to inflammatory regulation, e.g. , by the presence of the receptor at the surface of immune specific cells, and by agonist activation leading to changes in immune response.
  • the present disclosure provides associations between a GPR35 genotype, e.g., a genotype comprising a single nucleotide polymorphism (SNP) in GPR35, and an inflammatory disease, condition, or subclinical phenotype thereof. Practical applications of the associations between the provided genotypes and incidences of clinical and subclinical phenotypes in certain populations of individuals are described herein.
  • the genotypes of the present disclosure can be used to predict a risk that a subject will develop an inflammatory disease, condition, or a subclinical phenotype thereof.
  • the genotypes are also useful to predict whether a patient diagnosed with some form of an inflammatory disease will develop a severe form of the disease, such as a subclinical phenotype.
  • the genotypes disclosed herein are associated with an variation in an expression of GPR35, which in some cases, means the genotypes can be used to identify a patient who may be suitable for treatment with a targeted GPR35 therapy (e.g., a patient carrying a genotype associated with a decreased in GPR35 may be suitable for a treatment with an activator of GPR35).
  • a subject is administered a therapeutic agent (e.g., GPR35 modulator) provided the genotype disclosed herein is detected in a sample obtained from the subject.
  • a therapeutic agent e.g., GPR35 modulator
  • inflammatory diseases associated with the genotypes and/or treatments herein include inflammatory bowel diseases such as Crohn’s disease (CD) and ulcerative colitis (UC).
  • non-limiting examples of subclinical phenotypes include stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g.
  • ileum e.g., ileum, colon, ileocolonic, upper GI, rectum
  • perianal CD medically refractory UC, pancolitis, arthralgia, and spondylitis (Bmürew’s disease).
  • Further practical applications disclosed herein include laboratory- based methods of detecting the instant genotypes, such as quantitative PCR (qPCR) and other hybridization based assays, as well as sequencing methodologies. Additional exemplary applications include selecting an appropriate therapy (e.g. , GPR35 modulator) based on the presence or absence of a genotype, and monitoring treatment.
  • an appropriate therapy e.g. , GPR35 modulator
  • methods herein comprise treating the inflammatory disease or condition with a modulator of GPR35 activity or expression, such as a compound of Formula I-XXVI. Further aspects comprise selecting a patient for treatment after a determination that the patient comprises a certain GPR35 genotype, e.g., the patient comprises a single nucleotide polymorphism (SNP) in a GPR35 gene locus.
  • a modulator of GPR35 activity or expression such as a compound of Formula I-XXVI.
  • Further aspects comprise selecting a patient for treatment after a determination that the patient comprises a certain GPR35 genotype, e.g., the patient comprises a single nucleotide polymorphism (SNP) in a GPR35 gene locus.
  • SNP single nucleotide polymorphism
  • the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124; and (b) if the subject has the GPR35 genotype, administering to the subject a modulator of GPR35 activity or expression.
  • SNP single nucleotide polymorphism
  • a method of treating a subject having an inflammatory disease or condition comprising: administering to the subject a modulator of GPR35 activity or expression, provided a biological sample from the subject has been determined to comprise a GPR35 genotype, wherein the GPR35 genotype comprises a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124.
  • the inflammatory disease or condition comprises inflammatory bowel disease (IBD).
  • the inflammatory disease or condition comprises a condition indicative of developing a subclinical phenotype of inflammatory bowel disease.
  • the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bmürew’s disease), and any combination thereof.
  • the modulator of GPR35 activity or expression is an activator of GPR35.
  • the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.
  • determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject.
  • the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to a sequence selected from SEQ ID NOS: 63-124.
  • a primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid amplification assay, but does not amplify a corresponding wild type nucleic acid in a GPR35 genotype that does not comprise the nucleotide variance, wherein the nucleic acid comprises a sequence selected from SEQ ID NOS: 63-124; and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label.
  • the nucleotide variance comprises: (I) a“G” allele in rsl 13435444, (ii) an“A” allele in rs3749171, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an“A” allele in rs2975782, (vi) a“C” allele in rs3749172, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs4676396, (xi) an“A” allele in rs6735672, (xii) an“A” allele in rs34228697, (xiii) an“A” allele in rs46
  • nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises: (i) a“G” allele in rsl 13435444, (ii) an“A” allele in rs3749171, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an “A” allele in rs2975782, (vi) a“C” allele in rs3749172, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs467639
  • nucleic acid probe comprising a sequence selected from SEQ ID NOS: 63-124, and a detectable label. In some aspects, disclosed herein is a nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of a sequence selected from SEQ ID NOS: 32-124, and a detectable label.
  • a method for treating a subject having an inflammatory disease or condition comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulator of GPR35; wherein the GPR35 genotype composes a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124.
  • SNP single nucleotide polymorphism
  • determining comprises performing or having performed a genotyping assay on the biological sample from the subject.
  • the genotypmg assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to a sequence selected from SEQ ID NOS: 63-124.
  • the inflammatory disease or condition comprises inflammatory bowel disease (IBD).
  • the inflammatory disease or condition comprises a condition indicative of developing a subclinical phenotype of inflammatory bowel disease.
  • the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g., ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bmürew’s disease), and any combination thereof.
  • the modulator of GPR35 activity or expression is an activator of GPR35.
  • the modulator of GPR35 activity or expression comprises a compound selected from Formulas I -XXVI.
  • a compound selected from Formulas I-XXVI to treat a subject determined to comprise a condition indicative of developing an inflammatory bowel disease subcbnical phenotype, wherein the subclinical phenotype comprises stricturing, non- stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g.
  • a compound selected from Formulas I-XXVI to treat a subject comprising a GPR35 genotype comprising a single nucleotide polymorphism (SNP) positioned at nucleobase 16 in a sequence selected from SEQ ID NOS: 63-124.
  • SNP single nucleotide polymorphism
  • the method comprising: (a) determining or having determined the presence of a GPR35 genotype in a biological sample from the subject, wherein the GPR35 genotype comprises: (i) rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598,
  • the inflammatory disease or condition comprises inflammatory bowel disease, Crohn’s disease, ulcerative colitis, or a subclinical phenotype of inflammatory bowel disease, Crohn’s disease, or ulcerative colitis.
  • the modulator of GPR35 activity or expression is an activator of GPR35.
  • the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.
  • determining or having determined comprises performing or having performed a genotyping assay on the biological sample from the subject.
  • the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rs
  • a primer pair designed to anneal to a target nucleic acid in a GPR35 genotype comprising a nucleotide variance, wherein the primer pair selectively hybridizes to the target nucleic acid and amplifies the target nucleic acid in a nucleic acid
  • nucleic acid comprises (i) a sequence selected from SEQ ID NOS: 32-62, (ii) a sequence selected from SEQ ID NOS: 63-101, (iii) a sequence selected from SEQ ID NOS: 102-124, or (iv) or a combination of (i)-(iii); and wherein one or more primers of the primer pair comprises at least one non-naturally occurring nucleobase, peptide nucleic acid, or a label.
  • the nucleotide variance comprises: (i) a“G” allele in rsl 13435444, (ii) an“A” allele in rs3749171, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an“A” allele in rs2975782, (vi) a“C” allele in rs3749172, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs4676396, (xi) an“A” allele in rs6735672, (xii) an“A” allele in rs34228697, (xiii) an“A” allele in rs46
  • nucleic acid probe designed to detect a nucleotide variance within a GPR35 genotype, wherein detection is based on specific hybridization to the nucleotide variance, and wherein the nucleotide variance comprises: (i) a“G” allele in rsl 13435444, (ii) an“A” allele in rs374917l, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an “A” allele in rs2975782, (vi) a“C” allele in rs3749l72, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs46
  • nucleic acid probe comprising a sequence selected from SEQ ID NOS: 32-124, and a detectable label.
  • nucleic acid probe comprising at least about 10, 15, 20, or 25 contiguous nucleobases of a sequence selected from SEQ ID NOS: 32-124, and a detectable label.
  • a method for treating a subject having an inflammatory disease or condition comprising: (a) administering a modulator of GPR35 activity or expression to the subject, (b) determining whether the subject achieves a therapeutic benefit by determining the absence of a GPR35 genotype in a biological sample from the subject, (c) if the subject achieves the therapeutic benefit, then continuing administration of the modulator of GPR35 activity or expression, and if the subject does not achieve the therapeutic benefit, discontinuing administration of the modulator of GPR35 activity or expression; wherein the GPR35 genotype comprises: (i) rs!
  • the genotyping assay comprises specifically hybridizing a nucleic acid probe to the biological sample from the subject to detect the presence or absence of the GPR35 genotype, wherein the nucleic acid probe specifically hybridizes to (i) rsl l3435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rs
  • the inflammatory disease or condition comprises inflammatory bowel disease, Crohn’s disease, ulcerative colitis, or a subclinical phenotype of inflammatory bowel disease, Crohn’s disease, or ulcerative colitis.
  • the modulator of GPR35 activity or expression is an activator of GPR35.
  • the modulator of GPR35 activity or expression comprises a compound selected from Formulas I-XXVI.
  • a compound selected from Formulas I- XXVI to treat a subclinical phenotype of an inflammatory bowel disease comprising stricturing, non- stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g. , ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof.
  • a compound selected from Formulas I- XXVI to treat a subject comprising a GPR35 genotype comprising: (i) rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs
  • Ci-C * includes Ci-C 2 , C 1 -C 3 . . . Ci-C x .
  • Ci-C * refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).
  • An“alkyl” group refers to an aliphatic hydrocarbon group.
  • the alkyl groups may or may not include units of unsaturation.
  • the alkyl moiety may be a“saturated alkyl” group, which means that it does not contain any units of unsaturation (i.e. a carbon -carbon double bond or a carbon -carbon triple bond).
  • the alkyl group may also be an“unsaturated alkyl” moiety, which means that it contains at least one unit of unsaturation.
  • the alkyl moiety, whether saturated or unsaturated may be branched, straight chain, or cyclic.
  • The“alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as“1 to 6” refers to each integer in the given range; e.g. ,“1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
  • the alkyl group of the compounds described herein may be designated as C
  • “Ci-C 6 alkyl” indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n- pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl.
  • Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).
  • An“alkoxy” refers to a“-O-alkyl” group, where alkyl is as defined herein.
  • alkenyl moiety may be branched, straight chain, or cyclic (in which case, it would also be known as a“cycloalkenyl” group).
  • Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).
  • alkynyl refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atoms -CoC-R, wherein R refers to the remaining portions of the alkynyl group.
  • Non-limiting examples of an alkynyl group include -CoCH, -CoCCH 3 , -CoCCH 2 CH 3 and -CoCCH 2 CH 2 CH 3 .
  • The“R” portion of the alkynyl moiety may be branched, straight chain, or cyclic.
  • An alkynyl group can have 2 to 6 carbons.
  • Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).
  • “Dialkylamino” refers to a -N(alkyl) 2 group, where alkyl is as defined herein.
  • aromatic refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted.
  • aromatic includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).
  • aryl refers to an aromatic nng wherein each of the atoms forming the ring is a carbon atom.
  • Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).
  • Carboxy refers to -C0 2 H.
  • carboxy moieties may be replaced with a“carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety.
  • a carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group.
  • a compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound
  • a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group.
  • bioisostere s of a carboxylic acid include, but are not limited to,
  • cycloalkyl refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • heteroaryl or, alternatively,“heteroaromatic” refers to an aryl group that includes one or more nng heteroatoms selected from nitrogen, oxygen and sulfur.
  • An /V-containmg “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.
  • A“heterocycloalkyl” group or“heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur.
  • the radicals may be fused with an aryl or heteroaryl.
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring.
  • the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • halo or, alternatively,“halogen” means fluoro, chloro, bromo and iodo.
  • haloalkyl refers to an alkyl group that is substituted with one or more halogens.
  • the halogens may the same or they may be different.
  • Non -limiting examples of haloalkyls include -CH 2 C1, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , and the like.
  • fluoroalkyl and“fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms.
  • fluoroalkyls include - CF 3 , -CHF 2 , -CH 2 F, -CF1 2 CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , -CF(CH 3 ) 3 , and the like.
  • Non-limiting examples of fluoroalkoxy groups include -OCF 3 , -OCHF 2 , -OCH 2 F, -OCH 2 CF 3 , -OCF 2 CF 3 , -OCF 2 CF 2 CF 3 , - OCF(CH 3 ) 2 , and the like.
  • heteroalkyl refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g. , oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.
  • the heteroatom(s) may be placed at any interior position of the heteroalkyl group.
  • heteroalkyl may have from 1 to 6 carbon atoms.
  • bond or“single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • moiety refers to a specific segment or functional group of a molecule.
  • Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • substituent“R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.
  • the term“optionally substituted” or“substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C r C ( ,alkylalkyne.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, / -tolucncsulfonic acid, salicylic acid, and the like.
  • Exemplaiy salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates,
  • benzenesulfonates toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates,
  • methanesulfonates and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)).
  • Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine,
  • the term“about” or“approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e g , the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the given value. Where particular values are described in the application and claims, unless otherwise stated the term “about” should be assumed to mean an acceptable error range for the particular value.
  • compositions and methods when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose.
  • a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure, such as compositions for treating skin disorders like acne, eczema, psoriasis, and rosacea.
  • the terms“homologous,”“homology,” or“percent homology” when used herein to describe to an amino acid sequence or a nucleic acid sequence, relative to a reference sequence can be determined using the formula described by Karlin and Altschul (Proc. Natl. Acad.
  • the terms“increased,” or“increase” are used herein to generally mean an increase by a statically significant amount.
  • the terms“increased,” or“increase,” mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 10%, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, standard, or control.
  • Other examples of“increase” include an increase of at least 2-fold, at least 5-fold, at least 10- fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold or more as compared to a reference level.
  • “decreased” or“decrease” are used herein generally to mean a decrease by a statistically significant amount.
  • “decreased” or“decrease” means a reduction by at least 10% as compared to a reference level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g., absent level or non-detectable level as compared to a reference level), or any decrease between 10-100% as compared to a reference level.
  • a marker or symptom by these terms is meant a statistically significant decrease in such level.
  • the decrease can be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and is preferably down to a level accepted as within the range of normal for an individual without a given disease.
  • the terms“patient” or“subject” are used interchangeably herein, and encompass mammals.
  • mammal include, any member of the mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • the mammal is a human.
  • the term“animal” as used herein comprises human beings and non-human animals.
  • a“non-human animal” is a mammal, for example a rodent such as rat or a mouse.
  • Non-limiting examples of“biological sample” include any biological material from which nucleic acids and/or proteins can be obtained. As non-limiting examples, this includes whole blood, peripheral blood, plasma, serum, saliva, mucus, urine, semen, lymph, fecal extract, cheek swab, cells or other bodily fluid or tissue, including but not limited to tissue obtained through surgical biopsy or surgical resection.
  • the sample comprises tissue from the large and/or small intestine.
  • the large intestine sample comprises the cecum, colon (the ascending colon, the transverse colon, the descending colon, and the sigmoid colon), rectum and/or the anal canal.
  • the small intestine sample comprises the duodenum, jejunum, and/or the ileum.
  • a sample can be obtained through primary patient derived cell lines, or archived patient samples in the form of preserved samples, or fresh frozen samples.
  • “treatment” and“treating” as used herein refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition, prevent the pathologic condition, pursue or obtain good overall survival, or lower the chances of the individual developing the condition even if the treatment is ultimately unsuccessful.
  • subjects in need of treatment include those already with a disease or condition, as well as those susceptible to develop the disease or condition or those in whom the disease or condition is to be prevented.
  • the term“gene,” as used herein, refers to a segment of nucleic acid that encodes an individual protein or RNA (also referred to as a“coding sequence” or“coding region”), optionally together with associated regulatory region such as promoter, operator, terminator and the like, which may be located upstream or downstream of the coding sequence.
  • the term,“genotype” as disclosed herein refers to the chemical composition of polynucleotide sequences within the genome of an individual.
  • the genotype comprises single nucleotide variant (SNV), a single nucleotide polymorphism (SNP), or and indel (insertion or deletion, of a nucleobase within a polynucleotide sequence).
  • SNV single nucleotide variant
  • SNP single nucleotide polymorphism
  • indel insertion or deletion, of a nucleobase within a polynucleotide sequence.
  • a genotype for a particular SNV, SNP, or indel is heterozygous.
  • a genotype for a particular SNV, SNP, or indel is homozygous.
  • the term,“single nucleotide variant” or“single nucleotide variation” or SNV refers to a variation in a single nucleotide within a polynucleotide sequence.
  • the variation of an SNV may have multiple different forms.
  • a single form of an SNV is referred to as an“allele.”
  • An SNV can be mono-, bi-, tri, or tetra-allelic.
  • An SNV may include a“risk allele,” a“protective allele,” or neither.
  • a reference polynucleotide sequence reading 5’ to 3’ is TTACG.
  • a SNV at allele position 3 (of 5’-TTACG-3’) comprise a substitution of the reference allele,“A” to a non-reference allele,“C.” If the“C” allele of the SNV is associated with an increased probability of developing a phenotypic trait, the allele is considered a “risk” allele. However, the same SNV may also comprise a substitution of the“A” allele to a“T” allele at position 3. If the T allele of the SNV is associated with a decreased probability of developing a phenotypic trait, the allele is considered a“protective” allele.
  • the SNV may comprise a single nucleotide polymorphism (SNP), in some cases, which is an SNV observed in at least 1% of a given population.
  • the SNV is represented by an“rs” number, which refers to the accession of reference cluster of one more submitted SNVs in the dbSNP bioinformatics database as of the filing date of this patent application, and which is included within a sequence that comprises the total number of nucleobases from 5’ to 3’.
  • a SNV may be further defined by the position of the SNV (nucleobase) within the dbSNP sequence, the position of which is always with reference to 5’ length of the sequence plus 1.
  • a SNV is defined as the genomic position in a reference genome and the allele change (e.g. chromosome 7 at position 234,123,567 from G allele to A allele in the reference human genome build 37).
  • the allele change e.g. chromosome 7 at position 234,123,567 from
  • the SNV is defined as the genomic position identified with [brackets] in a sequence of Table 30 (e.g., SEQ ID NOS: 1-31).
  • the term,“indel,” as disclosed herein, refers to an insertion, or a deletion, of a nucleobase within a polynucleotide sequence.
  • An indel can be mono-, bi-, tri, or tetra- allelic.
  • An indel may be“risk,” a“protective,” or neither, for a phenotypic trait.
  • the indel is represented by an“rs” number, which refers to the accession of reference cluster of one more submitted indels in the dbSNP biomformatics database as of the filing date of this patent application, and which is included in a sequence that comprises the total number of nucleobases from 5’ to 3’ .
  • an indel may be further defined by the position of the insertion/deletion within the dbSNP sequence, the position of which is always with reference to the 5’ length of the sequence plus 1.
  • an indel is defined as the genomic position in a reference genome and the allele change.
  • the indel is defined as the genomic position identified with [brackets] in a sequence of Table 30 (e.g. , SEQ ID NOS: 1-31).
  • haplotype encompasses a group of one or more genotypes, SNVs, SNPs, or indels, which tend to be inherited together in a reference population.
  • a haplotype comprises particular SNVs, SNPs, or indels, and any SNV, SNP, or indel in linkage disequilibrium therewith.
  • “linkage disequilibrium,” or“LD,” as used herein refers to the non-random association of alleles or indels in different gene loci in a given population.
  • D’ comprises at least 0.20.
  • r 2 comprises at least 0.70.
  • the term,“serological marker,” as used herein refers to a biological marker found in semm that are associated with, or involved in disease pathology.
  • biological markers include proteins, nucleic acids, or other compounds with a physiological function in a subject.
  • serological markers comprising antibodies against microbial antigens or autoantibodies.
  • Non-limiting examples of serological markers comprising antibodies include anti-Saccharomyces cerevisiae (ASCA) anti-laminaribioside (ALCA), anti-chitobioside (ACCA), anti-mannobioside (AMCA), anti-laminarin (anti-L) and anti-chitin (anti- C), anti-outer membrane porin C (anti-OmpC), anti-Cbirl flagellin and anti-12 antibody, and anti neutrophil cytoplasmic autoantibodies (pANCA).
  • ASCA anti-Saccharomyces cerevisiae
  • ACA anti-laminaribioside
  • ACCA anti-chitobioside
  • AMCA anti-mannobioside
  • anti-L anti-laminarin
  • anti- C anti-outer membrane porin C
  • anti-OmpC anti-Cbirl flagellin and anti-12 antibody
  • pANCA anti neutrophil cytoplasmic autoantibodies
  • the term,“non-responsive” to a therapy refers to a subject not responding to the induction of a therapy (primary non-response), or loss of response during maintenance after a successful induction of the therapy (secondary loss of response).
  • the induction of a therapy comprises 1, 2, 3, 4, or 5, doses of the therapy.
  • loss of response is characterized by a reappearance of symptoms consistent with a flare after an initial response to the therapy.
  • Non-limiting examples of therapies include anti -tumor necrosis factor (TNF) alpha therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekmumab), Thalidomide, and Cytoxin.
  • TNF anti -tumor necrosis factor
  • vedolizumab anti-a4-b7 therapy
  • IL12p40 therapy ustekmumab
  • Thalidomide Thalidomide
  • Cytoxin Cytoxin.
  • a therapy that is administered to a subject who has been determined to be “non-responsive” to any of the above therapies may be referred to herein as a“secondary” or“second- line” therapeutic.
  • the term“anti-tumor necrosis factor (TNF) non-response,” as used herein, refers to a subject not responding to the induction of an anti-TNF therapy (primary non response), or loss of response during maintenance after a successful induction of the anti-TNF therapy (secondary loss of response).
  • the induction of the anti-TNF therapy comprises 1, 2, 3, 4, or 5, doses of the therapy.
  • loss of response is characterized by a reappearance of symptoms consistent with a flare after an initial response to the anti-TNF therapy.
  • the term“medically refractory,” or“refractory,” as used herein, refers to the failure of a standard treatment to induce remission of a disease.
  • the disease comprises an inflammatory disease disclosed herein.
  • a non-limiting example of refractory inflammatory disease includes refractory Crohn’s disease, and refractor ulcerative colitis (e.g., mrUC).
  • Non-limiting examples of standard treatment of inflammatory disease include
  • kits, compositions and methods for the treatment of IBD are kits, compositions and methods for the treatment of IBD. It is should be understood that kits and compositions disclosed herein may be used according to, or for, methods described herein. Conversely, methods disclosed herein may appropriately employ compositions disclosed herein.
  • the inflammatory condition or disease comprises a condition that involves chronic inflammation of the body caused by pathogens, viruses, foreign bodies or overactive immune responses.
  • the inflammatory disease comprises inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the primary forms of IBD are Crohn’s disease (CD) and ulcerative colitis (UC).
  • additional IBDs include microscopic colitis, diversion colitis, Behcet's disease and indeterminate colitis.
  • CD may affect almost any portion of the GI tract.
  • UC generally affects the anus and rectum.
  • Non-limiting symptoms of IBDs include diarrhea, abdominal pain, weight loss, and anemia.
  • there is a broad spectrum of prognoses for any given IBD making it difficult to decide on a standard or optimal course of treatment for any given patient.
  • inflammatory disease or conditions include, but are not limited to, rheumatoid arthritis, multiple sclerosis, psoriasis, chronic colitis, pancreatitis, leukopenia, and chronic asthma.
  • the subject presents fibrotic or fibrostenotic disease.
  • fibrotic or fibrostenotic diseases include colonic fibrosis, pulmonary fibrosis, primary sclerosing cholangitis, progressive systemic sclerosis, or fibrostenosis of a small and/or large intestine.
  • the subject is susceptible to, or is inflicted with, thiopurine toxicity, or a disease caused by thiopurine toxicity (such as pancreatitis or leukopenia).
  • the subject is non-responsive to a therapy comprising anti-TNF alpha therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, or Cytoxin.
  • the subject is a mammal.
  • the subject comprises a mouse, rat, guinea pig, rabbit, chimpanzee, or farm animal.
  • the subject is human.
  • the subject is diagnosed with the disease or condition disclosed herein.
  • Non-limiting methods for diagnosis using existing indices and scoring systems include Crohn's Disease Activity Index (CDAI), Ulcerative Colitis Disease Activity Index (UCDAI), guidelines from American College of Gastroenterology (ACG) and European Crohn's and Colitis Organization (ECCO), patient-reported outcomes (PRO-2), Harvey - Bradshaw Index, Van Hess Index, Perianal Disease Activity Index (PDAI), Rachmilewitz score, Mayo score, Powell-Tuck index, Patient Simple Clinical Colitis Activity Index (P-SCCAI), Lichtiger index, Seo index, Inflammatory Bowel Disease Questionnaire (IBDQ), Manitoba IBD Index, Crohn's Disease Endoscopic Index of Severity (CDEIS), Simple Endoscopic Score for Crohn Disease (SES- CD), Lewis score (capsule endoscopy), Rutgeert’s Score, and the Montreal Classification, and IBD questionnaire.
  • CDAI Crohn's Disease Activity Index
  • UDAI Ulcerative Colitis Disease Activity Index
  • ACG American College of Gastroenterology
  • the subject is not diagnosed with the disease or condition.
  • the subject is suffering from a symptom related to a disease or condition disclosed herein (e.g., abdominal pain, cramping, diarrhea, rectal bleeding, fever, weight loss, fatigue, loss of appetite, dehydration, and malnutrition, anemia, or ulcers).
  • a symptom related to a disease or condition disclosed herein e.g., abdominal pain, cramping, diarrhea, rectal bleeding, fever, weight loss, fatigue, loss of appetite, dehydration, and malnutrition, anemia, or ulcers.
  • the subject is susceptible to, or is inflicted with, thiopurine toxicity, or a disease caused by thiopurine toxicity (such as pancreatitis or leukopenia).
  • the subject is, or is suspected of being, non-re sponsive to a standard treatment (e.g., anti- TNF alpha therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, or Cytoxin).
  • a standard treatment e.g., anti- TNF alpha therapy, anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, or Cytoxin.
  • the subject is not responsive to the induction of said therapy.
  • the subject loses response to said standard treatment after a period of time during treatment.
  • G Protein-Coupled Receptor 35 (GPR35)
  • G Protein -Coupled Receptor 35 is a receptor for kynurenic acid, an intermediate in the tryptophan metabolic pathway. GPR35 mediates calcium mobilization and inositol phosphate production. GPR35, and nucleic acids encoding GPR35, are characterized by NCBI Entrez Gene ID 2859. Studies show that GPR35 is linked to inflammatory regulation, either by the presence of the receptor at the surface of immune specific cells, or by agonists activation leading to changes in immune response. Accordingly, it is hypothesized that GPR35, and nucleic acids encoding GPR35, play a role is inflammatory disease pathology making GPR35 an attractive therapeutic target to treat inflammatory diseases or conditions.
  • methods disclosed herein comprise assaying a biological sample for the presence of a single nucleotide polymorphism (SNP) in a GPR35 gene locus. In some instances, methods disclosed herein comprise detecting a presence of a SNP in a GPR35 gene locus. In some instances, methods disclosed herein comprise detecting an absence of a SNP in a GPR35 gene locus. In in some instances, the methods disclosed herein are used to treat a subject with an inflammatory disease or condition.
  • SNP single nucleotide polymorphism
  • GPR35 Single Nucleotide Polymorphism (GPR35 SNPS)
  • methods that comprise obtaining a biological sample from a subject; assaying for the presence of a single nucleotide polymorphism (SNP) in a GPR35 gene locus selected from Table 1, or a SNP in linkage disequilibrium therewith.
  • methods further comprise administering a therapeutic agent that modifies at least one of GPR35 expression and GPR35 activity, provided the presence of the SNP is determined.
  • Methods of detection disclosed herein are useful for determining the presence of a SNP.
  • the SNP may be in a coding region of GPR35 (e.g., an exon).
  • the SNP may be in a non-coding region of GPR35 (e.g., an intron).
  • the SNP may be in non-coding gene regulatory regions, thereby affecting GPR35 expression/activity.
  • a SNP in linkage disequilibrium with a GPR35 SNP is inherited with the GPR3 SNP.
  • the SNP in linkage disequilibrium may not be located in the GPR35 gene locus.
  • the SNP is defined as the genomic position identified with [brackets] in the polynucleotide sequence of any one of SEQ ID NOS: 1-31 shown in Table 30.
  • GPR35 SNPs that are associated with a risk of having, or developing, a disease or condition.
  • a presence of one or more SNPs from Table 1 in a sample obtained from a subject is indicative that the subject has, or will develop, the disease or condition.
  • a GPR35 SNP disclosed herein is associated with inflammatory bowel disease (IBD).
  • a GPR35 SNP disclosed herein is associated with Crohn’s disease (CD).
  • a GPR35 SNP disclosed herein is associated with ulcerative colitis (UC).
  • a GPR35 SNP disclosed herein is associated with stricturing. Stricturing may be described as the presence of a stricture or narrowed region of the intestine. The stricture may comprise scar tissue.
  • a GPR35 SNP disclosed herein is associated with penetrating.
  • Penetrating may be described as the presence of a fistula. Fistulae may occur between sections of the bowel or between the bowel and skin.
  • the stricturing, penetrating, and/or stricturing and penetrating disease is localized in the ileum, colon, or ileocolonic region of the intestine.
  • the GPR35 SNP is associated with stricturing, penetrating, and/or stricturing and penetrating disease is localized in the ileum, colon, or ileocolonic region of the intestine.
  • a GPR35 SNP disclosed herein is associated with perianal Crohn’s disease.
  • Perianal CD typically involves inflammation around the anus.
  • Perianal CD may be a sub-condition of CD or its own condition.
  • a GPR35 SNP disclosed herein is associated with pancolitis.
  • Pancolitis may be described as UC that is localized throughout the entire large intestine (right colon, left colon, transverse colon, descending colon and rectum).
  • the GPR35 SNP is associated with arthralgia.
  • arthralgia include osteoarthritis, rheumatoid arthritis, spondylitis, gout, post-traumatic arthritis, migratory arthritis, bursitis, and neuropathic arthropathy.
  • the GPR35 SNP is associated with medically refractory disease, characterized by the failure of a standard treatment to induce remission of a disease in a subject.
  • the disease comprises an inflammatory disease disclosed herein.
  • refractory inflammatory disease includes refractory Crohn’s disease (mrCD), and refractor ulcerative colitis (mrUC).
  • GPR35 SNPs that are associated with subclinical phenotype.
  • the subclinical phenotype is associated with one or the disease or conditions disclosed herein.
  • a presence of one or more SNPs from Table 1 in a sample obtained from a subject is indicative that the subject has, or will develop, the subclinical phenotype.
  • a subclinical phenotype may be a specific diagnosable disease or condition, or metric to measure disease progression that is characteristic of severe or unusual forms of disease
  • IBD subclinical phenotypes include, but are not limited to, non-stricturing disease, stricturing disease, stricturing and penetrating disease, and perianal Crohn’s disease (pCD).
  • Time to a first surgery, and time to second surgery are subclinical phenotypes used to identify subjects at risk for severe forms of disease.
  • a time to first surgery may be a time from a symptom of the inflammatory bowel disease to a surgery.
  • the time to first surgery may be a time from first diagnosis of the IBD to a time of a first surgery.
  • the time to second surgery may be a time from a first surgery to the time of a second surgery.
  • the first and/or second surgery may comprise surgery on at least a portion of the gastrointestinal tract of the subject.
  • Non-limiting surgeries include an intestinal resection, colectomy, perianal surgery, and stricturoplasty.
  • the symptom may be a symptom described herein.
  • the portion of the gastrointestinal tract may be selected from the anus, the colon, the large intestine, the small intestine, the stomach, and the esophagus.
  • GPR35 SNPs that are associated with a faster progression to surgery, as compared to an individual who does not carry the GPR35 SNP.
  • a faster progression to surgery is indicative of complicated disease, often resistant to therapy.
  • a presence of one or more SNPs from Table 1 in a sample obtained from a subject is indicative that the subject has, or will develop, complicated disease behavior characterized by a faster progression to a first and/or second surgery.
  • A“second surgery,” as used here, refers to the second surgical treatment of the same disease or disorder in the subject.
  • a GPR35 SNP disclosed herein is associated with a first time from a first symptom of the inflammatory bowel disease to a first surgery. In some instances, a GPR35 SNP disclosed herein is associated with a first time from a diagnosis of the inflammatory bowel disease to a first surgery. In some instances, a GPR35 SNP disclosed herein is associated with a time from an age to a first surgery. The first time may be about one year to about fifteen years. The first time may be about two years to about twelve years. The first time may be about four years to about ten years. The first time may be about four years to about eight years.
  • a GPR35 SNP disclosed herein is associated with a second time from a first surgery to a second surgery.
  • the second time may be about one year to about fifteen years.
  • the second time may be about two years to about twelve years.
  • the second time may be about four years to about ten years.
  • the second time may be about four years to about eight years.
  • the time to first surgery for patients carrying a risk allele may be about three years to about nine years.
  • the time to first surgery for patients carrying a risk allele may be about four years to about eight years.
  • the time to first surgery for patients for a risk allele may be about three years to about seven years.
  • the time to first surgery for patients for a risk allele may be about seven years.
  • the time to first surgery for patients homozygous for a non-risk minor allele may be about ten years.
  • the time to first surgery for patients homozygous for a non-risk minor allele may be greater than about ten years.
  • the time to first surgery for patients homozygous for a non-risk minor allele may be at least about ten years.
  • GPR25 SNPs associated with non-response or loss of response to a standard therapy.
  • a presence of one or more SNPs from Table 1 in a sample obtained from a subject is indicative that the subject has, or will develop, non response or loss of response to a standard therapy.
  • standard therapy of inflammatory disease include glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy
  • a GPR35 SNP disclosed herein is associated with a combination of IBD, CD, UC, mrUC, mrCD, stricturing, penetrating, perianal CD, arthalgia, non-response to a standard therapy, and pancolitis.
  • GPR35 SNP is associated with the expression of serological markers.
  • a presence of one or more SNPs from Table 1 in a sample obtained from a subject is indicative that the subject has, or will develop, a disease or condition or subtype of the disease or condition, associated with a presence of a microbiome.
  • Non-limiting examples of serological markers include mti-Saccharomyces cerevisiae (ASCA) anti-laminaribioside (ALCA), anti-chitobioside (ACCA), anti-mannobioside (AMCA), anti-laminarin (anti-L) and anti- chitin (anti-C), anti -outer membrane porin C (anti-OmpC), anti-Cbirl flagellin and anti-12 antibody, and anti -neutrophil cytoplasmic autoantibodies (pANCA).
  • ASCA mti-Saccharomyces cerevisiae
  • ACA anti-laminaribioside
  • ACCA anti-chitobioside
  • AMCA anti-mannobioside
  • anti-L anti-laminarin
  • anti-C anti-outer membrane porin C
  • pANCA anti-neutrophil cytoplasmic autoantibodies
  • the minor allele correlates to a reduced risk of a patient exhibiting a corresponding phenotype. In some embodiments, if OR>l, the minor allele correlates to an increased risk of a patient exhibiting a corresponding phenotype.
  • the SNP occurs in an expression quantitative trait locus (eQTL).
  • eQTL expression quantitative trait locus
  • Expression quantitative trait loci are genomic loci that affect expression of an mRNA or protein.
  • a SNP in an eQTL results in increased GPR35 expression.
  • a SNP in an eQTL results in decreased GPR35 expression.
  • the eQTL is a local eQTL, e.g., within the gene locus.
  • the eQTL is a distant eQTL, e.g., outside of the gene locus.
  • the eQTL is on a different chromosome than the GPR35 locus, referred to herein as a trans eQTL.
  • the eQTL is on the same chromosome as the GPR35 locus, referred to herein as a cis eQTL.
  • the eQTL is tissue-independent.
  • the eQTL is tissue-dependent.
  • methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of rectum tissue.
  • methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of anal tissue.
  • methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of colon tissue.
  • methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of intestinal tissue. In some instances, methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of stomach tissue. In some instances, methods disclosed herein comprise assaying for or detecting a SNP in an eQTL of esophageal tissue.
  • QTL mapping may be performed by analysis of variance (ANOVA), standard interval mapping, composite interval mapping, and family -based pedigree mapping.
  • eQTL shows that the minor allele codes for upregulation of the GPR35 mRNA in small bowel tissue and the association shows that minor allele is a risk for UC, IBD and CD. In other cases the minor allele may code for upregulation of the gene but the major allele might be the risk allele.
  • a subject comprising administrating of therapeutic effective amount of one or more therapeutic agents to the subject.
  • the one or more therapeutic agents is administered to the subject alone (e.g., standalone therapy).
  • the one or more therapeutic agents is administered in combination with an additional agent.
  • the therapeutic agent is a first-line therapy for the disease or condition.
  • the therapeutic agent is a second-line, third-line, or fourth-line therapy, for the disease or condition.
  • the subject to be treated with the therapeutic agent is selected for treatment based on a presence of one or more single nucleotide polymorphisms (SNPs) detected in a sample obtained from the subject.
  • SNPs single nucleotide polymorphisms
  • the one or more SNPs comprises a SNP at the GPR35 gene, or genetic locus.
  • the one or more SNPs comprises a SNP in linkage disequilibrium with rs3749171 as determined by an r 2 of at least about 0.70, about 0.75, about 0.80, about 0.85, about 0.85, about 0.90, or about 1.0.
  • the SNP comprises one or more of rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402, rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs34826997, rs6437364, rs2011743,
  • the SNP comprises a risk allele provided in [brackets] within any one or SEQ ID NOS: 1-31 shown in Table 30. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. In some embodiments, a GPR35 genotype comprises the SNP. In some embodiments, the SNP is detected in a biological sample obtained from the subject using one or more of the methods of detection described herein.
  • compositions, kits and methods disclosed herein may comprise a therapeutic agent or use thereof.
  • Thetherapeutic agents disclosed herein are useful for the treatment of the inflammatory diseases or conditions, or symptoms of the inflammatory diseases or conditions disclosed herein.
  • Non limiting examples of classes of therapeutic agents used to treat the inflammatory diseases or conditions disclosed herein include anti-inflammatory mediators (e.g small molecule and large molecule), steroids, and tumor necrosis factor (TNF) inhibitors.
  • Non-limiting examples of therapeutic agents used to treat IBD include azathioprine, methotrexate, 6-mercaptopurine, prednisone, mesalazinc. and budesonide.
  • Methods disclosed herein that comprise the use of a therapeutic agent may substitute or supplement the use of the therapeutic agent with a nutritional-based therapy, nature-based therapy, or diet-based therapy.
  • a nutritional-based therapy for example, subjects with anemia may benefit from parenteral iron
  • methods comprise administering a B vitamin, fat-soluble vitamin, an essential fatty acid, magnesium, zin, selenium, or a combination thereof. In some instances, methods comprise administering Plantago ovata, curcumin, wormwood, or a combination thereof. In some instances, methods comprise administering an antibiotic. Conversely, in some instances, methods comprise administering a microbe, e.g., a fecal microbiota transplant.
  • compositions, kits and methods disclosed herein may comprise and/or utilize a therapeutic agent or use thereof, wherein the therapeutic agent is effective to modify expression and/or activity of GPR35 (e.g., modulator of GPR35).
  • therapeutic agents that modify expression and/or activity of GPR35 may also be referred to herein as GPR35 -targeting agents.
  • compositions, kits and methods disclosed herein may comprise and/or utilize a therapeutic agent or use thereof, wherein the therapeutic agent modifies expression and/or activity of a protein that functions upstream or downstream of a pathway that involves GPR35.
  • the modulator of GPR35 is effective to increase or activate the activity or expression of GPR35 in the subject (e.g., agonist or partial agonist).
  • the modulator of GPR35 is effective to decrease or reduce the activity or expression of GPR35 (e.g., antagonist or partial antagonist).
  • the therapeutic agent is an antagonist of GPR35.
  • the antagonist acts as an inverse agonist.
  • Non-limiting examples of inverse agonists are ML145 and ML144.
  • the therapeutic agent is an allosteric modulator of GPR35.
  • Methods disclosed herein may comprise administering GPR35 -targeting agents alone.
  • methods disclosed herein may comprise administering GPR35 -targeting agents along with another therapeutic agent disclosed herein, a nutritional -based therapy, a nature-based therapy, a diet-based therapy, or a combination thereof.
  • the subject has a SNP that is associated with, or causes, an increased expression of GPR35. In some instances, the subject has a SNP that is associated with, or causes increased activity of GPR35. In some instances, the SNP is associated with, or causes and increase expression of GPR35. In some instances, the SNP is associated with, or causes an increase activity of GPR35. In these instances, it may be suitable to use a GPR35 antagonist to bring GPR35 activity back to a normal level, e.g., that of a person without the IBD of the subject.
  • the subject has a SNP that is associated with, or causes decreased expression of GPR35.
  • the subject has a SNP is associated with, or causes, decreased activity of GPR35.
  • the SNP is associated with, or causes, a decrease in expression of GPR35.
  • the SNP is associated with, or causes, decreased activity of GPR35.
  • it may be suitable to use a GPR35 agonist to bring GPR35 activity back to a normal level, e.g., that of a person without the IBD of the subject.
  • the therapeutic agent is a small molecule drag.
  • a small molecule drug may be a chemical compound.
  • a small molecule has a molecular weight less than about 1,000 Da, or less than about 900 Da, or less than about 800 Da.
  • a small molecule has a molecular weight from about 50 Da to about 1,000 Da.
  • the therapeutic agent is a large molecule drug.
  • Large molecule drugs generally comprise a peptide or nucleic acid.
  • the large molecule drug may comprise an antibody or antigen binding antibody fragment.
  • the therapeutic agent comprises a small molecule and a large molecule.
  • the therapeutic agent may comprise an antibody-drug conjugate.
  • the therapeutic agent is a small molecule that binds GPR35.
  • the small molecule that binds GPR35 is a GPR35 agonist.
  • the small molecule that binds GPR35 is a GPR35 partial agonist.
  • the small molecule that binds GPR35 is a GPR35 antagonist.
  • the small molecule that binds GPR35 is a GPR35 partial agonist.
  • the small molecule that binds GPR35 is a compound of Formula (I):
  • each R 5 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -
  • each R 7 is independently selected from H and Ci_ 6 alkyl
  • each R 8 is independently selected from halogen, -OH, -OR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -
  • 9heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen, C
  • each R 9 is independently selected from C
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ 8cycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, -N(R n ) 2 , and -C(0)0R 12 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C
  • R 12 is independently selected from H and Ci_ 6 alkyl
  • R 13 is selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci- 6 alkyl-C 3-8 cycloalkyl, phenyl, - Ci_ 6 alkyl -phenyl, and C 2.9 heteroaryl;
  • each R 14 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ gcycloalkyl, phenyl, -C
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, 4, or 5;
  • q 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (II):
  • X 1 , X 2 , Y 1 , and Y 2 are independently selected from O, NR 13 , and C(R 14 ) 2 ;
  • R 1 and R 2 are independently selected from -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -
  • R 3 is selected from -OH
  • each R 4 and R 5 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -OC(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , CY f .alkyl -C ⁇ alkyl-OH, - Ci_ 6 alkyl-OR 9 , -Ci_ 6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2.6 alkynyl, C
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ 8cycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ s alkyl-phenyl, -Ci_ 6alkyl-C 2.9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cycloal
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-g cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2 _9heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C
  • R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 3 _ r, alkyl, oxo, and -C(0)0H;
  • each R 11 is independently selected from H and Ci_ 6 alkyl
  • each R 12 is independently selected from H and Ci_ 6 alkyl
  • each R 13 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-g cycloalkyl, -Ci_ 6 alkyl-C 3 _ 8cycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl;
  • each R 14 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-g cycloalkyl, -Ci_ 6 alkyl-C 3 _ 8cycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2 _9heterocycloalkyl, -Ci_6alkyl-C 2 -9heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2 _9heteroaryl;
  • n 1, 2, 3, 4, or 5;
  • n 1, 2, 3, 4, or 5;
  • p 0, 1, 2, or 3;
  • q 0, 1, 2, or 3;
  • the small molecule that binds GPR35 is a compound of Formula (III):
  • X 1 and X 2 are independently selected from O, NR 13 , and C(R 14 ) 2 ;
  • R 1 and R 2 are independently selected from -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , - C(0)R 9 , -C(0)OR 10 , -OC(0)R 9 , -C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -
  • R 3 and R 4 are independently selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , and -
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2 g hctcroaryk and -Ci_ 6 alkyl-C 2 9 heteroaryl, wherein C
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -CY ⁇ , alkyl -CY scycloalkyl, phenyl, -CY 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C -9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, CY 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from CY r.alkyl, oxo, and -C(0)0H;
  • each R 11 is independently selected from H and CYr.alk l:
  • each R 12 is independently selected from H and CYr.alkyl:
  • each R 13 is independently selected from H, CY 6 alkyl, CY 6 haloalkyl, C 3-8C ycloalkyl, -CYr.alkyl -CY scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl; and
  • each R 14 is independently selected from H, CY 6 alkyl, CY 6 haloalkyl, C 3-8 cycloalkyl, -CY 6 alkyl-C 3 _ scycloalkyl, phenyl, -CY 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -CY 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -CY 6 alkyl-C 2-9 heteroaryl;
  • the small molecule that binds GPR35 is a compound of Formula (IV):
  • X 1 and X 2 are independently selected from 0, NR 13 , and C(R 14 ) 2 ;
  • R 1 and R 2 are independently selected from -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , - R 3 and R 4 are independently selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , CY ( , alkyl.
  • each R 9 is independently selected from C
  • each R 10 is independently selected from H, CY 6 alkyl, CY 6 haloalkyl, C 3-8 cycloalkyl, -CY ⁇ , alkyl -CY gcycloalkyl, phenyl, -CY 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein CY 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C -9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from CY ( alk l oxo, and -C(0)0H;
  • each R 11 is independently selected from H and CY ( alk ⁇ i:
  • each R 12 is independently selected from H and CY ( alkvl:
  • each R 13 is independently selected from H, CY 6 alkyl, CY 6 haloalkyl, C 3-8 cycloalkyl, -CY, alkyl -CY gcycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl; and
  • each R 14 is independently selected from H, CY 6 alkyl, CY 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ ( ,alkyl-C 3 _ gcycloalkyl, phenyl, -CY 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl;
  • the small molecule that binds GPR35 is a compound of Formula (V):
  • R 1 and R 2 are independently selected from H, CY 6 alkyl, CY 6 haloalkyl, C 3.gC ycloalkyl, -CY 6 alkyl- C 3.gC ycloalkyl, phenyl, -CYr, alkyl -phenyl, and C 2 -9heteroaryl; each R 3 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , - S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)
  • each R 9 is independently selected from C
  • Ci_ 6 alkyl, phenyl, -Ci_ 6 alkyl-phenyl, -Ci_ 6alkyl-C 2.9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C -9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3.8 cycloalkyl, -C(0)R 12 , and -C(0)0R 12 ;
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C -9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ r.alkyl, oxo, and -C(0)0H;
  • each R 11 is independently selected from H and CYr.alkyl:
  • each R 12 is independently selected from H and CY 6 alkyl
  • p 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (VI):
  • X is selected from O, NR 13 , and C(R 14 ) 2 ;
  • R 1 and R 2 are independently selected from -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , - C(0)R 9 , -C(0)OR 10 , -OC(0)R 9 , -C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , - NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , Ci_ 6 alkyl, -Ci_ 6 alkyl-OH, -Ci_ 6 alkyl-OR 9 , and -Ci_ 6 alkyl- N(R 10 ) 2 ; R 3 and R 4 are independently selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9
  • each R 5 and each R 6 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , - S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , - C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C , alkyl.
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C -9 heteroaryl, wherein C .alkyl.
  • phenyl, -Ci_ 6 alkyl-phenyl, -Ci_ 6alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -CV favoralkyl-C 2 _ ⁇ ,hctcroaiyl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cycloalkyl, -C(0)R 12 , and -C(0)0R 12 ;
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8C yeloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;
  • each R 11 is independently selected from H and CVi, alkyl:
  • each R 12 is independently selected from H and CYi.alkyl:
  • R 13 is selected from H, C
  • each R 14 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -C
  • p 0, 1, 2, 3, or 4;
  • q 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (VII):
  • R 1 is selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3.8 cycloalkyl, phenyl, -
  • each R 3 and each R 4 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , - S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , - C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C, alkyl.
  • each R 9 is independently selected from CY,, alkyl.
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ (alkyl. oxo, and -C(0)0H;
  • each R 11 is independently selected from H and Ci_ 6 alkyl
  • each R 12 is independently selected from H and Ci_ 6 alkyl
  • p 0, 1, 2, 3, or 4;
  • q 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (VIII):
  • X is selected from -0-, -S-, and -S0 2 -;
  • R 1 is selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3-8 cycloalkyl, phenyl, - Ci_ 6 alkyl -phenyl, and C 2-9 heteroaryl;
  • each R 2 and each R 3 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -
  • R 4 is selected from
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.g cycloalkyl, -Ci_ 6 alkyl-C 3 _ 8cycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6 alkyl-phenyl, -Ci_ 6alkyl-C 2.9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cycloalky
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3 8 cycloalkyl, -C
  • each R 11 is independently selected from H and Ci_ 6 alkyl
  • each R 12 is independently selected from H and C
  • p 0, 1, 2, 3, or 4;
  • q 0, 1, 2, or 3;
  • the small molecule that binds GPR35 is a compound of Formula (IX):
  • X is selected from -0- and -S-;
  • R 1 is selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 ,
  • R 2 is selected from
  • each R 3 is independently selected from halogen, -CN, -OH, N0 2 , -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6 alkyl-phenyl, -Ci_ 6alkyl-C 2.9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cycloal
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-g cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2 9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, C
  • each R 11 is independently selected from H and Ci_ 6 alkyl
  • each R 12 is independently selected from H and Ci_ 6 alkyl
  • p 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (X):
  • R 1 is selected from
  • each R 2 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -
  • each R 3 is independently selected from H, halogen, -CN, -OH, N0 2 , -OR 9 , -SR 9 , -N(R 10 ) 2 , - S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , - C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C 1-6 alkyl, - C , f alkyl-OH, -Ci_ 6 alkyl-OR 9 , -Ci_ 6 alkyl-N(R 10 ) 2 , C 2 6 alkenyl, C 2 6 alky
  • each R 10 is independently selected from H, Ci_ 6 alkyl, C
  • each R 11 is independently selected from H and C’ , alkyl:
  • each R 12 is independently selected from H and Ci_ 6 alkyl
  • p 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (XI):
  • X is selected from -0-, -S-, and -S0 2 -;
  • R 1 is selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -OC(0)R 9 , -C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , - NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C , alkyl.
  • each R 2 and each R 3 is independently selected from halogen, -CN, -OH,
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci.
  • each R 10 is independently selected from H, Ci_ 6 alkyl, C
  • each R 11 is independently selected from H and C’ , alkyl:
  • each R 12 is independently selected from H and Ci_ 6 alkyl
  • p 0, 1, 2, 3, or 4;
  • q 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (XII):
  • X is selected from -0-, -S-, -NR 13 -, and -C(R 14 ) 2 -;
  • each R 1 is independently selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , - S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , -C(O)N(R 10 ) 2 , .
  • R 2 is selected from H and Ci_ 6 alkyl
  • each R 3 and each R 4 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , - S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , - C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C 1-6 alkyl, - Ci- 6 alkyl-OH, -Ci_ 6 alkyl-OR 9 , -Ci_ 6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2.6 alkynyl, Ci
  • each R 10 is independently selected from H, Ci_ 6 alkyl, C
  • each R 11 is independently selected from H and C’ .alkyl:
  • each R 12 is independently selected from H and Ci_ 6 alkyl
  • R 13 is selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci. 6 alkyl-C 3.8C ycloalkyl, phenyl, - Ci_ 6 alkyl -phenyl, and C 2.9 heteroaryl;
  • R 14 is selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci. 6 alkyl-C3_ 8 cycloalkyl, phenyl, - Ci- 6 alkyl-phenyl, C 2-9 heterocycloalkyl, -Ci_ 6 alkyl-C 2 _9heterocycloalkyl, C 2-9 heteroaryl, and - Ci- 6 alkyl-C 2 _9heteroaryl;
  • p 0, 1, 2, 3, or 4;
  • q 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (XIII):
  • X 1 and X 2 are independently -0-, -S-, or -NR 13 -;
  • R 1 is selected from R 2 i
  • each R 3 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , - S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C 1-6 alkyl, -C ⁇ alkyl-OH, - Ci_ 6 alkyl-OR 9 , -Ci_ 6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2.6 alkynyl, CiJialoal
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6 alkyl-phenyl, -Ci_ 6alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cycloal
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8C ycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2 -9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;
  • p 0, 1 or 2;
  • the small molecule that binds GPR35 is a compound of Formula (XIV):
  • R 1 and R 2 are independently selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C , alkyl.
  • each R 3 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , - S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C M , alkyl.
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C -9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6 alkyl-phenyl, -Ci_ 6alkyl-C 2.9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C -9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cycloal
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8C yeloalkyl, -C m ( , alkyl -CN scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;
  • each R 11 is independently selected from H and CY alkyl:
  • each R 12 is independently selected from H and CY ( alkyl: and
  • p 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (XV):
  • X is selected from -0-, -S-, and -S0 2 -;
  • Y is N or CR 2 ;
  • each R 3 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , - S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C 1-6 alkyl, -C ⁇ alkyl-OH, - Ci- 6 alkyl-OR 9 , -Ci_ 6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, Ci_ 6 halo
  • each R 9 is independently selected from C , alkyl.
  • -Ci_ 6alkyl-C 2.9 heterocycloalkyl, C 2.9 heteroaryl, and -C M6 alkyl-C -9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3.8 cycloalkyl, -C(0)R 12 , and -C(0)0R 12 ;
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -C
  • each R 11 is independently selected from H and CY ( , alkyl:
  • each R 12 is independently selected from H and CY ( , alkyl: and
  • p 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (XVI):
  • X is selected from -0-, -S-, and -NR -;
  • R 1 is selected from
  • each R 2 and each R 7 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , - S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , - C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , Ci_ 6 alkyl, - Ci_ 6 alkyl-OH, -Ci_ 6 alkyl-OR 9 , -Ci_ 6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2.6 alkynyl, Ci
  • R 3 and R 4 are independently selected from H and Ci_ 6 alkyl
  • R 5 is selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3-8 cycloalkyl, phenyl, -
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ s alkyl-phenyl, -Ci_ 6alkyl-C 2.9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cyclo
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C i (alkyl. oxo, and -C(0)0H;
  • each R 11 is independently selected from H and CV ( , alkyl:
  • each R 12 is independently selected from H and C’ , alkyl:
  • R 13 is selected from H, C’ , alkyl. C haloalkyl. C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3.8 cycloalkyl, phenyl, - Ci-ealkyl -phenyl, and C 2.9 heteroaryl; p is 0, 1, 2, or 3; and
  • q 0, 1, 2, or 3;
  • the small molecule that binds GPR35 is a compound of Formula (XVII):
  • X is selected from -0-, -S-, and -S0 2 -;
  • R 1 is selected from
  • each R 2 and each R 3 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -
  • each R 9 is independently selected from C i_,,alkyl.
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -C m( , alkyl -C 3 _ 8cycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 3 _ 6alkyl, oxo, and -C(0)0H;
  • each R 11 is independently selected from H and CY ( alkyl:
  • each R 12 is independently selected from H and CY ( alkyl:
  • the small molecule that binds GPR35 is a compound of Formula (XVIII):
  • R 1 is selected from
  • R 2 is independently selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -
  • each R 3 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , - S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -OC(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , Ci-ealkyl, -Ci_ 6 alkyl-OH, - and -
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6 alkyl-phenyl, -Ci_ 6alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cycloal
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ 8cycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5- or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 3 _ 6alkyl, oxo, and -C(0)OH; each R 11 is independently selected from H and Ci_ 6 alkyl;
  • each R 12 is independently selected from H and C
  • p 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (XIX):
  • X is selected from -0-, -S-, and -NR 13 -;
  • R 1 is selected from H and Ci_ 6 alkyl
  • R 2 is independently selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , - S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C , alkyl.
  • each R 4 is independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , - S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C l ( ,alky l.
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl, wherein C
  • phenyl, -Ci_ s alkyl-phenyl, -Ci_ 6alkyl-C 2.9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cycloalkyl, -C(0)R 12 , and -C(0)0R 12 ;
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;
  • each R 11 is independently selected from H and C
  • each R 12 is independently selected from H and C
  • R 13 is selected from H, C
  • p 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (XX):
  • X is selected from -O- and -C(R 14 ) 2 -;
  • R 1 is selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -OC(0)R 9 , -C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , - NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C,.,, alkyl.
  • R 2 is selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -OC(0)R 9 , -C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , - NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , O m( , alkyl.
  • each R 3 and each R 4 is selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , - S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -OC(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C ⁇ alkyl, -C ⁇ alkyl-OH, - Ci_ 6 alkyl-OR 9 , -Ci_ 6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2.6 alkynyl, Ci_ 6
  • each R 10 is independently selected from H, Ci_ 6 alkyl, C
  • each R 11 is independently selected from H and C’ , alkyl:
  • each R 12 is independently selected from H and Ci_ 6 alkyl
  • each R 14 is independently selected from H, halogen, C
  • the small molecule that binds GPR35 is a compound of Formula (XXI):
  • X 1 and X 2 are independently selected from -0- and -S-;
  • each R 1 and each R 2 are independently selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , - S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , - C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C 1-6 alkyl, - Ci_ 6 alkyl-OH, -Ci_ 6 alkyl-OR 9 , -Ci_ 6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, Ci
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ 8cycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6 alkyl-phenyl, -Ci_ 6alkyl-C 2 -9heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cycl
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-g cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2 9 lictcroaiyl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from C 3 _ (alkyl. oxo, and -C(0)0H;
  • each R 11 is independently selected from H and Ci_ 6 alkyl
  • each R 12 is independently selected from H and Ci_ 6 alkyl
  • R 13 is selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3-8 cycloalkyl, phenyl, - Ci_ 6 alkyl -phenyl, and C 2-9 heteroaryl;
  • p 0, 1, 2, or 3;
  • q 0, 1, 2, or 3;
  • the small molecule that binds GPR35 is a compound of Formula (XXII):
  • X is selected from -0- and -S-;
  • R 1 , R 2 , and R 3 are independently selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , - S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -0C(0)R 9 , - C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C 1-6 alkyl, -
  • each R 4 is selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2 9 heteroaryl, and -C
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-g cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -C
  • each R 11 is independently selected from H and Ci_ 6 alkyl
  • each R 12 is independently selected from H and Ci_ 6 alkyl
  • p 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (XXIII):
  • each X is independently selected from -O- and -S-;
  • R 1 is selected from
  • each R 2 is selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -
  • -Ci_ 6 alkyl-OR 9 - Ci_ 6 alkyl-N(R 10 ) 2 , C 2.6 alkenyl, C 2-6 alkynyl, Ci-ehaloalkyl, C 3.8 cycloalkyl, and -Ci-ealkyl-CY scycloalkyl;
  • R 3 is selected from H, Ci_ 6 alkyl, CY 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3-8 cycloalkyl, phenyl, - Ci_ 6 alkyl -phenyl, and C 2.9 heteroaryl; each R 4 and each R 5 are independently selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 ,
  • R 6 is selected from C 3 g cycloalkyl, C 2 9 heterocycloalkyl, C 2 9 heteroaryl, and phenyl, wherein C gcycloalkyl, C 2 9 heterocycloalkyl, C 2 9 heteroaryl, and phenyl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R U ) 2 , CY f , alkyl, C 3 _ gcycloalkyl, -C(0)R 12 , and -C(0)0R 12 ;
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ gcycloalkyl, phenyl, -CY 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C -9 heteroaryl, wherein CY f, alkyl, phenyl, -CY 6 alkyl-phenyl, -Ci_ 6alkyl-C 2.9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3 -gcycloalky
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -C i_ ( ⁇ alk ⁇ l-C 3 _ gcycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;
  • each R 11 is independently selected from H and CY ( alkyl:
  • each R 12 is independently selected from H and CY alkyl:
  • p 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (XXIV):
  • X is selected from -O- and -S-; R 1 is selected from
  • each R 2 is selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -
  • each R 3 is selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -
  • R 4 is selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, and C 3-8 cycloalkyl;
  • R 5 is selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3.8 cycloalkyl, phenyl, - Ci_ 6 alkyl -phenyl, and C 2.9 heteroaryl;
  • R 6 is independently selected from H, Ci_ 6 alkyl, C
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ 8cycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6 alkyl-phenyl, -Ci_ 6alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cycloalky
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ 8cycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from CY (alkyl. oxo, and -C(0)0H;
  • each R 11 is independently selected from H and CY ( , alkyl
  • each R 12 is independently selected from H and C , alkyl:
  • p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
  • the small molecule that binds GPR35 is a compound of Formula (XXV):
  • X is selected from CR 2 or N;
  • R 1 is selected from C 3.8 cycloalkyl, C 2 -9heterocycloalkyl, C 2 -9heteroaryl, and phenyl, wherein C 3 _ 8cycloalkyl, C 2-9 heterocycloalkyl, C 2-9 heteroaryl, and phenyl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R U ) 2 , CY f , alkyl, C 3 _ scycloalkyl, -C(0)R 12 , and -C(0)OR 12 ;
  • each R 2 and each R 6 is selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , - S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -OC(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , C , alkyl.
  • R 3 and R 4 are independently selected from H, halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -NHS(0) 2 R 9 , -S(O) 2 N(R 10 ) 2 , -C(0)R 9 , -C(0)OR 10 , -OC(0)R 9 , -C(O)N(R 10 ) 2 , - OC(O)N(R 10 ) 2 , -NR 10 C(O)N(R 10 ) 2 , -NR 10 C(O)R 9 , -NR 10 C(O)OR 9 , Ci-ealkyl, -C’u.alkvl-OH.
  • Ci_ 6 alkyl-OR 9 -Ci_ 6 alkyl-N(R 10 ) 2 , C 2-6 alkenyl, C 2.6 alkynyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, and - Ci- 6 alkyl -C 3.8 cycloalkyl ;
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ 8cycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_ 6 alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl, wherein C
  • phenyl, -Ci_ s alkyl-phenyl, -Ci_ 6alkyl-C 2.9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C 2-9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 alkyl, C 3-8 cycloalkyl, -C(0)R 12 , and -C(0)OR 12 ; each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2 -9heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6alkyl -phenyl, and
  • each R 11 is independently selected from H and Ci_ 6 alkyl
  • each R 12 is independently selected from H and C’ , alkyl
  • p 0, 1, 2, 3, 4, 5, or 6;
  • q 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is a compound of Formula (XXVI):
  • R 1 is selected from
  • each R 2 is selected from halogen, -CN, -OH, -OR 9 , -SR 9 , -N(R 10 ) 2 , -S(0)R 9 , -S(0) 2 R 9 , -
  • each R 9 is independently selected from Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3.8 cycloalkyl, -Ci_ 6 alkyl-C 3 _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, C 2.9 heterocycloalkyl, -Ci_6alkyl-C 2 _9heterocycloalkyl, C 2 -9heteroaryl, and -Ci_ 6 alkyl-C 2 -9heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6 alkyl-phenyl, -Ci_ 6alkyl-C 2-9 heterocycloalkyl, C 2.9 heteroaryl, and -Ci_ 6 alkyl-C -9 heteroaryl are optionally substituted with one or two groups independently selected from Ci_ 6 alkyl, -OR 11 , -N(R n ) 2 , Ci_ 6 al
  • each R 10 is independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3-8 cycloalkyl, -O m( , alkyl -C ; _ scycloalkyl, phenyl, -Ci_ 6 alkyl-phenyl, and C 2-9 heteroaryl, wherein Ci_ 6 alkyl, phenyl, -Ci_ 6 alkyl -phenyl, and C 2 -9heteroaryl are optionally substituted with one or two groups independently selected from halogen, Ci_ 6 alkyl, and -N(R n ) 2 ; or two R 10 and the nitrogen atom to which they are attached are combined to form a 5 - or 6-membered heterocycloalkyl ring optionally substituted with one, two, or three groups independently selected from Ci_ 6alkyl, oxo, and -C(0)0H;
  • each R 11 is independently selected from H and C
  • each R 12 is independently selected from H and C
  • p 0, 1, 2, 3, or 4;
  • the small molecule that binds GPR35 is selected from zaprinast, lodoxamide, bufrolin, TC-G 1001, nedocromil, PSB-13253, 6-bromo-7-hydroxy-8-nitro-3-(lH- tetrazol-5-yl)-2H-chromen-2-one, 6-bromo-7-hydroxy-8-nitro-2-oxo-2H-chromene-3-carboxylic acid, 7-deshydroxypyrogallin-4-carboxylic acid (DCA), morin, cromolyn, T 3 , reverse T 3 YE-210, cromoglicic acid, nedocromil, pamoic acid, and tyrphostin-51.
  • DCA 7-deshydroxypyrogallin-4-carboxylic acid
  • the small molecule that binds GPR35 is selected from pamoic acid, amlexanox, furosemide, doxantrazole, kynurenic acid, DHICA, cyclic guanosine monophosphate (cGMP), 2,3,5-THB, ellagic acid, . LPA species, and YE120.
  • the small molecule that binds GPR35 is selected from ML-145, ML-194, and ML- 144.
  • the small molecule that binds GPR35 is selected from:
  • the small molecule that binds GPR35 is selected from:
  • the small molecule that binds GPR35 is selected from:
  • therapeutic agents described herein are provided in the form of a pharmaceutical composition.
  • the pharmaceutical composition may comprise one or more pharmaceutically acceptable salts, excipients or vehicles.
  • Pharmaceutically acceptable salts, excipients, or vehicles include, but are not limited to, carriers, excipients, diluents, antioxidants, preservatives, coloring, flavoring and diluting agents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, tonicity agents, cosolvents, wetting agents, complexing agents, buffering agents, antimicrobials, and surfactants.
  • Neutral buffered saline or saline mixed with serum albumin are exemplary appropriate carriers.
  • compositions may include antioxidants such as ascorbic acid; low molecular weight polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as Tween, pluronics, or polyethylene glycol (PEG).
  • antioxidants such as ascorbic acid
  • proteins such as serum albumin, gelatin, or immunoglobulins
  • hydrophilic polymers such as polyvinylpyrrolidone
  • amino acids such as glycine, glutamine, asparagine, arginine or lysine
  • suitable tonicity enhancing agents include alkali metal halides (in some cases, preferably sodium or potassium chloride), mannitol, sorbitol, and the like.
  • Suitable preservatives include benzalkonium chloride, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid and the like. Hydrogen peroxide also may be used as preservative.
  • Suitable cosolvents include glycerin, propylene glycol, and PEG.
  • Suitable complexing agents include caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxy-propyl-beta-cyclodextrin.
  • Suitable surfactants or wetting agents include sorbitan esters, polysorbates such as polysorbate 80, tromethamine, lecithin, cholesterol, tyloxapal, and the like.
  • the buffers may be conventional buffers such as acetate, borate, citrate, phosphate, bicarbonate, or Tris-HCl.
  • Acetate buffer may be about pH 4-5.5, and Tris buffer may be about pH 7-8.5. Additional pharmaceutical agents are set forth in Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, ed., Mack Publishing Company, 1990.
  • the composition may be in liquid form, lyophilized form or freeze-dried form.
  • the composition may include one or more lyoprotectants, excipients, surfactants, high molecular weight structural additives and/or bulking agents (see, for example, U.S. Patent Nos. 6,685,940, 6,566,329, and 6,372,716).
  • a lyoprotectant is included, which is a non-reducing sugar such as sucrose, lactose or trehalose .
  • the amount of lyoprotectant generally included is such that, upon reconstitution, the resulting formulation will be isotonic, although hypertonic or slightly hypotonic formulations also may be suitable.
  • lyoprotectant concentrations for sugars e.g., sucrose, lactose, trehalose
  • sugars e.g., sucrose, lactose, trehalose
  • concentrations for sugars in the pre- lyophilized formulation are from about 10 mM to about 400 mM.
  • a surfactant is included, such as for example, nonionic surfactants and ionic surfactants such as polysorbates (e.g., polysorbate 20, polysorbate 80); poloxamers (e.g., poloxamer 188); polyethylene glycol) phenyl ethers (e.g., Triton); sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl-or stearyl-sarcosine; linoleyl, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palm
  • Exemplary amounts of surfactant that may be present in the pre-lyophilized formulation are from about 0.001-0.5%.
  • High molecular weight structural additives may include for example, acacia, albumin, alginic acid, calcium phosphate (dibasic), cellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, dextran, dextrin, dextrates, sucrose, tylose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, disodium hydrogen phosphate, disodium phosphate, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, liquid glucose, compressible sugar, magnesium aluminum silicate, maltodextrin, polyethylene oxide, polymethacrylates, povidone, sodium alginate, tragacanth microcrystalline cellulose, starch, and
  • compositions may be suitable for parenteral administration.
  • Exemplary compositions are suitable for injection or infusion into an animal by any route available to the skilled worker, such as intraarticular, subcutaneous, intravenous, intramuscular, intraperitoneal, intracerebral
  • a parenteral formulation typically will be a sterile, pyrogen-free, isotonic aqueous solution, optionally containing pharmaceutically acceptable preservatives.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringers' dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishes, such as those based on Ringer's dextrose, and the like.
  • Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. See generally, Remington's Pharmaceutical Science, 16th Ed., Mack Eds., 1980, which is incorporated by reference in its entirety.
  • compositions described herein may be formulated for controlled or sustained delivery in a manner that provides local concentration of the product (e.g., bolus, depot effect) and/or increased stability or half-life in a particular local environment.
  • Compositions may comprise particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc. , as well as agents such as a biodegradable matrix, injectable microspheres, microcapsular particles, microcapsules, bioerodible particles beads, liposomes, and implantable delivery devices that provide for the controlled or sustained release of the active agent which then may be delivered as a depot injection.
  • Such sustained-or controlled-delivery means are known and a variety of polymers have been developed and used for the controlled release and delivery of drugs.
  • Such polymers are typically biodegradable and biocompatible.
  • Polymer hydrogels including those formed by complexation of enantiomeric polymer or polypeptide segments, and hydrogels with temperature or pEI sensitive properties, may be desirable for providing drug depot effect because of the mild and aqueous conditions involved in trapping bioactive protein agents. See, for example, the description of controlled release porous polymeric microparticles for the delivery of pharmaceutical compositions in WO 93/15722.
  • Suitable materials for this purpose include polylactides (see, e.g., U.S. Patent No.
  • Other biodegradable polymers include
  • Sustained -release compositions also may include liposomes, which may be prepared by any of several methods known in the art (see, e.g., Eppstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688-92 (1985)).
  • the carrier itself, or its degradation products, should be nontoxic in the target tissue and should not further aggravate the condition. This may be determined by routine screening in animal models of the target disorder or, if such models are unavailable, in normal animals.
  • Microencapsulation of recombinant proteins for sustained release has been performed successfully with human growth hormone (rhGH), interferon-(rhlFN-), interleukin-2, and MN rgpl20.
  • rhGH human growth hormone
  • interferon-(rhlFN-) interferon-(rhlFN-)
  • interleukin-2 interleukin-2
  • MN rgpl20 MN rgpl20.
  • the degradability of this polymer may be depending on its molecular weight and composition.
  • Lewis “Controlled release of bioactive agents from lactide/glycolide polymer,” in: M. Chasin and R. Langer (Eds.), Biodegradable Polymers as Drug Delivery Systems (Marcel Dekker: New York, 1990), pp. 1-41.
  • Additional examples of sustained release compositions include, for example, EP 58,481A, U.S. Patent No. 3,887,699, EP 158,277A, Canadian Patent No. 1176565, U. Sidman et al, Biopolymers 22, 547 [1983], R. Langer et al , Chem. Tech. 12, 98 [1982], Sinha et al, J. Control. Release 90, 261 [2003], Zhu et al , Nat.
  • Bioadhesive polymers are also contemplated for use in or with compositions of the present disclosure.
  • Bioadhesives are synthetic and naturally occurring materials able to adhere to biological substrates for extended time periods.
  • Carbopol and polycarbophil are both synthetic cross-linked derivatives of poly(acrylic acid).
  • Bioadhesive delivery systems based on naturally occurring substances include for example hyaluronic acid, also known as hyaluronan.
  • Hyaluronic acid is a naturally occurring mucopolysaccharide consisting of residues of D -glucuronic and N-acetyl-D- glucosamine.
  • Hyaluronic acid is found in the extracellular tissue matrix of vertebrates, including in connective tissues, as well as in synovial fluid and in the vitreous and aqueous humor of the eye. Esterified derivatives of hyaluronic acid have been used to produce microspheres for use in delivery that are biocompatible and biodegradable (see, for example, Cortivo et al . , Biomaterials (1991) 12:727-730; EP 517,565; WO 96/29998; Ilium et al, J. Controlled Rel. (1994) 29: 133-141).
  • Both biodegradable and non-biodegradable polymeric matrices may be used to deliver compositions of the present disclosure, and such polymeric matrices may comprise natural or synthetic polymers. Biodegradable matrices are preferred. The period of time over which release occurs is based on selection of the polymer. Typically, release over a period ranging from between a few hours and three to twelve months is most desirable.
  • Exemplary synthetic polymers which may be used to form the biodegradable delivery system include: polymers of lactic acid and glycolic acid, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, poly-vinyl halides,
  • polyvinylpyrrolidone polyglycolides, polysiloxanes, polyanhydrides, polyurethanes and co-polymers thereof, poly(butic acid), poly(valeric acid), alkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose, cellulose triacetate, cellulose sulphate sodium salt, poly(methyl methacrylic esters, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate
  • Exemplary natural polymers include alginate and other polysaccharides including dextran and cellulose, collagen, chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins, copolymers and mixtures thereof. In general, these materials degrade either by enzymatic hydrolysis or exposure to water in vivo, by surface or bulk erosion.
  • the polymer optionally is in the form of a hydrogel (see, for example, WO 04/009664, WO 05/087201, Sawhney, et al, Macromolecules, 1993, 26, 581-587) that can absorb up to about 90% of its weight in water and further, optionally is cross-linked with multi-valent ions or other polymers.
  • a hydrogel see, for example, WO 04/009664, WO 05/087201, Sawhney, et al, Macromolecules, 1993, 26, 581-587
  • Delivery systems also include non-polymer systems that are lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as mono-di-and tri-glycerides; hydrogel release systems; silastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; partially fused implants; and the like.
  • Specific examples include, but are not limited to: (a) erosional systems in which the product is contained in a form within a matrix such as those described in U.S. Patent Nos. 4,452,775, 4,675,189 and 5,736, 152 and (b) diffusional systems in which a product permeates at a controlled rate from a polymer such as described in U.S. Patent Nos. 3,854,480, 5, 133,974 and 5,407,686.
  • Liposomes containing the product may be prepared by methods known methods, such as for example (DE 3,218,121; Epstein et al,
  • compositions may be administered locally via implantation into the affected area of a membrane, sponge, or other appropriate material on to which a therapeutic agent disclosed herein has been absorbed or encapsulated.
  • a therapeutic agent disclosed herein may be directly through the device via bolus, or via continuous administration, or via catheter using continuous infusion.
  • Formulations containing a therapeutic agent disclosed herein may be administered orally.
  • Formulations administered in this fashion may be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules.
  • a capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized.
  • Additional agents may be included to facilitate absorption of a selective binding agent. Diluents, flavorings, low melting point waxes, vegetable oils, lubncants, suspending agents, tablet disintegrating agents, and binders also may be employed.
  • Another preparation may involve an effective quantity of a therapeutic agent disclosed herein in a mixture with non-toxic excipients which are suitable for the manufacture of tablets.
  • excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.
  • Suitable and/or preferred pharmaceutical formulations may be determined in view of the present disclosure and general knowledge of formulation technology, depending upon the intended route of administration, delivery format, and desired dosage. Regardless of the manner of administration, an effective dose may be calculated according to patient body weight, body surface area, or organ size. Further refinement of the calculations for determining the appropriate dosage for treatment involving each of the formulations described herein are routinely made in the art and is within the ambit of tasks routinely performed in the art. Appropriate dosages may be ascertained through use of appropriate dose-response data. [00145] In general, methods disclosed herein comprise administering a therapeutic agent by oral administration. However, in some instances, methods comprise administering a therapeutic agent by intraperitoneal injection.
  • methods comprise administering a therapeutic agent in the form of an anal suppository.
  • methods comprise administering a therapeutic agent by intravenous (“i.v”) administration. It is conceivable that one may also administer therapeutic agents disclosed herein by other routes, such as subcutaneous injection, intramuscular injection, intradermal injection, percutaneous administration, intranasal administration, and intralymphatic injection.
  • a single nucleotide polymorphism in some embodiments are methods of selecting a subject based on a presence of a single nucleotide polymorphism (SNP) in a biological sample obtained from the subject; and treating the subject with a therapeutic agent described herein (e.g., modulator of GPR35).
  • the SNP is detected using the methods of detection described herein.
  • the subject is treated in accordance with the methods of treatment described herein.
  • the SNP comprises any one, or combination of, SNPs described herein, including, but not limited to Tables 1-29.
  • methods comprising obtaining a biological sample from a subject; assaying for the presence of at least one SNP comprising a risk allele at rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, r
  • LD is determined by an r 2 value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0.
  • the SNP comprises a risk allele provided in [brackets] within SEQ ID NO: 1-31.
  • the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124.
  • a GPR35 genotype comprises the SNP.
  • the risk allele at rsl 13435444 comprises a“G.”
  • the risk allele at rs3749171 comprises an“A.”
  • the risk allele at rs4676406 comprises an“A.”
  • the risk allele at rs4676399 comprises a“C.” In some embodiments, the risk allele at rs2975782 comprises an“A.” In some embodiments, the risk allele at rs3749172 comprises a “C.” In some embodiments, the risk allele at rs79844648 comprises a“G.” In some embodiments, the risk allele at rs4676402 comprises a“A” In some embodiments, the risk allele at rs2975780 comprises an“A.” In some embodiments, the risk allele at rs4676396 comprises an“A.” In some embodiments, the risk allele at rs6735672 comprises an“A.” In some embodiments, the risk allele at rs34228697 comprises an“A.” In some embodiments, the risk allele at rs4676401 comprises an“A.” In some embodiments, the risk allele at rs2975786 comprises a“G.” In some embodiments, the risk allele at rs29
  • a method of treating an IBD in a subject comprising administering a therapeutically effective amount of a therapeutic agent that targets GPR35 signaling, provided the subject has an increased or a decreased levels of GPR35 as determined by detecting in a sample obtained from the subject having a risk allele at a SNP at a GPR35 locus associated with IBD comprising rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944
  • the SNP comprises a risk allele provided in [brackets] within SEQ ID NO: 1-31 as shown in Table 30. In some embodiments, the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124. In some embodiments, a GPR35 genotype comprises the SNP.
  • the risk allele at rsl 13435444 comprises a“G.” In some embodiments, the risk allele at rs3749171 comprises an“A.” In some embodiments, the risk allele at rs4676406 comprises an“A.” In some embodiments, the risk allele at rs4676399 comprises a“C.” In some embodiments, the risk allele at rs2975782 comprises an “A.” In some embodiments, the risk allele at rs3749172 comprises a“C.” In some embodiments, the risk allele at rs79844648 comprises a“G.” In some embodiments, the risk allele at rs4676402 comprises a“A” In some embodiments, the risk allele at rs2975780 comprises an“A.” In some embodiments, the risk allele at rs4676396 comprises an“A.” In some embodiments, the risk allele at rs6735672 comprises an“A.” In some embodiments, the risk allele at r
  • the risk allele at rs4676405 comprises a“G.” In some embodiments, the risk allele at rs2953154 comprises a“G.” In some embodiments, the risk allele at rs6732874 comprises an “A.” In some embodiments, the risk allele at rs55862430 comprises a“G.” In some embodiments, the risk allele at rsl2621598 comprises an“A.” In some embodiments, the risk allele at rs55919442 comprises an“A.” In some embodiments, the risk allele at rs74991608 comprises an“A.” In some embodiments, the risk allele at rs34826997 comprises a“T.” In some embodiments, the risk allele at rs6437364 comprises an“A.”
  • the IBD may comprise Crohn’s disease, ulcerative colitis, or perianal Crohn’s disease.
  • the increased or decreased levels of GPR35 detected in the sample may be relative to a level of GPR35 in a control subject without the IBD
  • methods of treating a subject with Crohn’s disease who is predicted to develop perianal Crohn’s disease comprising administering a therapeutically effective therapeutic agent to the subject, provided a SNP at a GPR35 locus associated with perianal Crohn’s disease is detected in a sample obtained from the subject, the SNP comprising a risk allele at rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648,
  • SNP is positioned within a sequence selected from SEQ ID NOS: 32-124.
  • a GPR35 genotype comprises the SNP.
  • the risk allele at rsl 13435444 comprises a“G.” In some embodiments, the risk allele at rs3749171 comprises an“A.” In some embodiments, the risk allele at rs4676406 comprises an“A.” In some embodiments, the risk allele at rs4676399 comprises a “C.” In some embodiments, the risk allele at rs2975782 comprises an“A.” In some embodiments, the risk allele at rs3749172 comprises a“C.” In some embodiments, the risk allele at rs79844648 comprises a“G.” In some embodiments, the risk allele at rs4676402 comprises a“A” In some embodiments, the risk allele at rs2975780 comprises an“A.” In some embodiments, the risk allele at rs4676396 comprises an“A.” In some embodiments, the risk allele at rs6735672 comprises an“A.”
  • the risk allele at rs34228697 comprises an“A.” In some embodiments, the risk allele at rs4676401 comprises an“A.” In some embodiments, the risk allele at rs2975786 comprises a “G” In some embodiments, the risk allele at rs4676346 comprises a“A.” In some embodiments, the risk allele at rs6437356 comprises a“A.” In some embodiments, the risk allele at rs6745185 comprises a“C.” In some embodiments, the risk allele at rs4676407 comprises a“G” In some embodiments, the risk allele at rs2953156 comprises a“G.” In some embodiments, the risk allele at rs4335944 comprises a“C.” In some embodiments, the risk allele at rs73999973 comprises a“A.” In some embodiments, the risk allele at rs4676410 comprises an“A.” In some embodiments, the risk allele
  • IBD Inflammatory Bowel Disease
  • the method comprising administering a therapeutically effective amount of therapeutic agent targeting GPR35 signaling, provided the subject has an increased or a decreased level of GPR35 as determined by contacting a sample obtained from the subject with a probe (e.g., oligonucleotide primer or probe) targeting a SNP at a GPR35 locus associated with IBD and detecting binding between the SNP and the probe, wherein the SNP comprises a risk allele at rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs46763
  • a probe e.g., oligonucleotide primer or
  • the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124.
  • a GPR35 genotype comprises the SNP.
  • the risk allele at rsl 13435444 comprises a“G.”
  • the risk allele at rs3749171 comprises an“A.”
  • the risk allele at rs4676406 comprises an“A.”
  • the risk allele at rs4676399 comprises a“C.”
  • the risk allele at rs2975782 comprises an “A.”
  • the risk allele at rs3749172 comprises a“C.”
  • the risk allele at rs79844648 comprises a“G.”
  • the risk allele at rs4676402 comprises a“A”
  • the risk allele at rs2975780 comprises an“A.”
  • the risk allele at rsl 13435444 comprises a“G.”
  • the risk allele at rs3749171 comprises an“A.”
  • the risk allele at rs4676405 comprises a“G.” In some embodiments, the risk allele at rs2953154 comprises a“G.” In some embodiments, the risk allele at rs6732874 comprises an “A.” In some embodiments, the risk allele at rs55862430 comprises a“G.” In some embodiments, the risk allele at rsl2621598 comprises an“A.” In some embodiments, the risk allele at rs55919442 comprises an“A.” In some embodiments, the risk allele at rs74991608 comprises an“A.” In some embodiments, the risk allele at rs34826997 comprises a“T.” In some embodiments, the risk allele at rs6437364 comprises an“A.” In some embodiments, LD is determined by an r 2 value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0. Non-limiting examples of probes are provided in SEQ ID NOS
  • IBD Inflammatory Bowel Disease
  • the method comprising administering a therapeutically effective amount of therapeutic agent targeting GPR35 signaling, provided the subject has an increased or a decreased level of GPR35 as determined by contacting a sample obtained from the subject with a probe targeting a SNP at a GPR35 locus associated with IBD and detecting binding between the SNP and the probe, wherein the SNP comprises rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407
  • LD is determined by an r 2 value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0.
  • the SNP comprises a risk allele provided in [brackets] within SEQ ID NO: 1-31, as shown in Table 30.
  • the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124.
  • a GPR35 genotype comprises the SNP.
  • the inflammatory disease or condition comprises an inflammatory disease, fibrostenotic disease, and/or fibrotic disease.
  • inflammatory diseases include diseases of the GI tract, liver, gallbladder, and joints.
  • the inflammatory disease inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), or rheumatoid arthritis.
  • the disease or condition comprises fibrosis, fibrostenosis, or a fibrotic disease, either isolated or in combination with an inflammatory disease.
  • An exemplary fibrotic disease is PSC.
  • a subtype of the disease or condition is diagnosed in the subject.
  • Non-limiting examples of subtypes of IBD include, stricturing disease, penetrating disease, stricturing and penetrating disease, obstructive disease, refractory disease, or another complicated form of IBD.
  • the subject is diagnosed with, or predicted to develop, one disease or condition, two disease or conditions, three disease or conditions, or more.
  • a disease a disease or condition in a subject comprising: (a) obtaining a biological sample from a subject; (b) subjecting the sample to an assay configured to detect a presence, absence, or level, of a GPR35 risk genotype; (c) diagnosing the subject with the disease or condition, provided the presence, absence, or level of the GPR35 risk genotype is detected in the sample obtained from the subject.
  • the GPR35 risk genotype is detected using one or more methods of detection, kits and/or compositions disclosed herein.
  • the subject is treated by administering a therapeutically effective amount of a therapeutic agent and/or additional agent disclosed herein (e.g., activator of GPR35) to the subject, provided the subject is diagnosed with the disease or condition.
  • the GPR35 risk genotype comprises rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73
  • the GPR35 risk genotype comprises at least about 1 single nucleotide polymorphism (SNP), about 2 SNPs, about 3 SNPs, about 4 SNPs, about 5 SNPs, about 6 SNPs, about 7 SNPs, about 8 SNPs, about 9 SNPs, about 10 SNPs, about 11 SNPs, or more.
  • the genotype comprises one or more SNPs provided in any one of Tables 1-29.
  • the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124.
  • a subject will develop an inflammatory disease a disease or condition
  • the method comprising: (a) obtaining a sample from a subject; (b) subjecting the sample to an assay configured to detect a presence, absence, or level, of a GPR35 risk genotype; (c) predicting that the subject will develop the disease or condition, provided the presence, absence, or level of the GPR35 risk genotype is detected in the sample obtained from the subject.
  • the GPR35 risk genotype is detected using one or more methods of detection, kits and/or compositions disclosed herein.
  • the subject is treated by administering a therapeutically effective amount of a therapeutic agent (e.g., activator of GPR35) and/or additional agent disclosed herein to the subject, provided the subject is predicted to develop the disease or condition.
  • a therapeutic agent e.g., activator of GPR35
  • the GPR35 risk genotype comprises rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G,
  • the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124.
  • the GPR35 risk genotype comprises one or more SNPs in linkage disequilibrium with rs79844648G as determined by an r 2 value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0.
  • the GPR35 risk genotype comprises at least about 1 single nucleotide polymorphism (SNP), about 2 SNPs, about 3 SNPs, about 4 SNPs, about 5 SNPs, about 6 SNPs, about 7 SNPs, about 8 SNPs, about 9 SNPs, about 10 SNPs, about 11 SNPs, or more.
  • the genotype comprises one or more SNPs provided in any one of Tables 1-29.
  • the inflammatory disease or condition comprises a fibrostenotic disease, and/or fibrotic disease
  • Non-limiting examples of inflammatory diseases include diseases of the GI tract, liver, gallbladder, and joints.
  • the inflammatory disease IBD, CD, UC, systemic lupus erythematosus (SLE), or rheumatoid arthritis.
  • the disease or condition comprises fibrosis, fibrostenosis, or a fibrotic disease, either isolated or in combination with an inflammatory disease.
  • An exemplary fibrotic disease is PSC.
  • the inflammatory disease or condition comprises an inflammatory disease, fibrostenotic disease, and/or fibrotic disease.
  • inflammatory diseases include diseases of the GI tract, liver, gallbladder, and joints.
  • the disease or condition comprises fibrosis, fibrostenosis, or a fibrotic disease, either isolated or in combination with an inflammatory disease.
  • An exemplary fibrotic disease is PSC.
  • subtypes of IBD include, stricturing disease, penetrating disease, stricturing and penetrating disease, obstructive disease, refractory disease, or another complicated form of IBD.
  • a disease or condition or a subtype of a disease or condition comprising: (a) obtaining a sample from a subject;
  • the subject is treated by administering a therapeutically effective amount of a therapeutic agent and/or additional agent disclosed herein to the subject, provided the subject is disease or condition is characterized as severe, complicated, or refractory disease.
  • the GPR35 risk genotype comprises rs l 13435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G, rsl2621598A, rs
  • the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124.
  • the GPR35 risk genotype is associated with a risk that a subject has, or will develop, inflammatory bowel disease (IBD), Crohn’s disease (CD), or ulcerative colitis (UC), as determined by a P value of at most about 1.0 x 10 6 , about 1.0 x 10 7 , about 1.0 x 10 8 , about 1.0 x 10 9 , about 1.0 x 10 10 , about 1.0 x 10 20 , about 1.0 x 10 30 , about 1.0 x 10 40 , about 1.0 x 10 50 , about 1.0 x 10 60 , about 1.0 x 10 70 , about 1.0 x 10 80 , about 1.0 x 10 90 , or about 1.0 x 10 100 .
  • IBD inflammatory bowel disease
  • CD Crohn’s disease
  • UC ulcerative colitis
  • the GPR35 risk genotype is associated with a risk that the subject has, or will develop, a subclinical phenotype or subtype of the disease or condition as determined by a P value of at most about 1.0 x 10 ⁇ 6 , about 1.0 x 10 ⁇ 7 , about 1.0 x 10 8 , about 1.0 x 10 9 , about 1.0 x 10 10 , about 1.0 x lO 20 , about 1.0 x 10 30 , about 1.0 x 10 40 , about 1.0 x 10 ⁇ 5 °, about 1.0 x 10 60 , about 1.0 x 10 70 , about 1.0 x 10 ⁇ 80 , about 1.0 x 10 ⁇ 9 °, or about 1.0 x 10 10 °.
  • Non-limiting examples of subtypes and/or subclinical phenotypes of Crohn’s disease include stricturing, penetrating, stricturing and penetrating, disease phenotypes, non-response or loss of response to treatment with a standard therapy (e.g., corticosteroid, anti-TNF therapy, thiopurine therapy), perianal Crohn’s disease, and faster progression to a First Surgery or a Second Surgery.
  • the GPR35 risk genotype comprises one or more SNPs in linkage disequilibrium with rs79844648G as determined by an r 2 value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0.
  • the GPR35 risk genotype comprises at least about 1 single nucleotide polymorphism (SNP), about 2 SNPs, about 3 SNPs, about 4 SNPs, about 5 SNPs, about 6 SNPs, about 7 SNPs, about 8 SNPs, about 9 SNPs, about 10 SNPs, about 11 SNPs, or more.
  • the genotype comprises one or more SNPs provided in any one of Tables 1-29.
  • methods comprise assaying for the presence of a SNP disclosed herein in a biological sample obtained from a subject.
  • methods of detecting a presence, absence, or level, of a genotype or biomarker in a sample obtained from a subject are useful for the diagnosis, prognosis, monitoring of disease progression, selection for treatment, monitoring of treatment, and/or treatment of inflammatory bowel disease (e.g., Crohn’s disease (CD), ulcerative colitis (UC), and the like) disclosed herein.
  • inflammatory bowel disease e.g., Crohn’s disease (CD), ulcerative colitis (UC), and the like
  • the subject presents a symptom of an inflammatory disease or condition described herein (e.g., IBD, CD, UC).
  • IBD symptoms include abdominal pain, diarrhea, vomiting, weight loss, fever, anemia, skin rash, arthritis, and inflammation of the eyes.
  • the subject presents at least two symptoms of an IBD.
  • the subject presents at least three symptoms of an IBD.
  • methods comprise assaying for the presence of a SNP disclosed herein in a sample of a subject that has a family history (at least one family member) of IBD.
  • the subject has been diagnosed with the IBD.
  • the IBD comprises gluten intolerance.
  • the IBD comprises gluten sensitivity.
  • the IBD comprises Crohn’s disease, ulcerative colitis, microscopic colitis, diversion colitis, and Behcet's disease. In some instances, it is difficult to diagnose the IBD, and the IBD may be referred to as indeterminate colitis.
  • methods disclosed herein comprise obtaining a biological sample from the subject.
  • the biological sample is obtained directly from the subject (e.g., at the point of care, directly from the subject).
  • the biological sample is obtained indirectly from the subject (e.g at a biobank, healthcare facility, directly from the subject).
  • the biological sample may comprise DNA.
  • the biological sample may comprise RNA.
  • the biological sample may comprise a cell-free nucleic acid.
  • the biological sample may comprise a peptide.
  • the biological sample may be a biological fluid.
  • the biological sample may be a biological fluid that contains a nucleic acid.
  • Non-limiting examples of biological fluids useful for the methods disclosed herein are whole blood, serum, plasma, urine, and saliva Additional biological fluids, e.g., ocular fluid, sinus fluid, lymphatic fluid, cerebrospinal fluid, could conceivably be used for methods disclosed herein.
  • the biological sample comprises whole cells.
  • the biological sample may comprise a buccal swab or skin swab.
  • the biological sample is non-fluidic.
  • the biological sample may comprise hair or a hair follicle.
  • Methods, kits and systems disclosed herein are generally suitable for analyzing a biological sample obtained from a subject.
  • Biological samples may be obtained through surgical biopsy or surgical resection. In some instances, a needle biopsy aspiration can be used to collect the a biological sample from a subject.
  • Biological samples may be obtained by a fluid draw, swab or fluid collection.
  • Biological samples may be obtained through primary patient derived cell lines, or archived patient samples in the form of FFPE (Formalin fixed, paraffin embedded) samples, or fresh frozen samples.
  • Biological samples may comprise whole blood, peripheral blood, plasma, serum, saliva, cheek swab, or other bodily fluid or tissue.
  • the sample may comprise tissue from the large and/or small intestine.
  • the large intestine sample may comprise the cecum, colon (the ascending colon, the transverse colon, the descending colon, and the sigmoid colon), rectum and/or the anal canal.
  • the small intestine sample may comprise the duodenum, jejunum, and/or the ileum.
  • the sample may also comprise a blood sample.
  • the sample may comprise serum.
  • the sample may comprise tissue and blood.
  • the abnormal tissue and/or cell sample is microdissected to reduce the amount of normal tissue contamination prior to extraction of genomic nucleic acid or pre-RNA for use in the methods of the invention.
  • Such enrichment and/or purification may be accomplished according to methods, such as needle microdissection, laser microdissection, fluorescence activated cell sorting, and immunological cell sorting.
  • nucleic acids are extracted using any technique that does not interfere with subsequent analysis.
  • this technique uses alcohol precipitation using ethanol, methanol or isopropyl alcohol.
  • this technique uses phenol, chloroform, or any combination thereof.
  • this technique uses cesium chloride.
  • this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA.
  • this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich.
  • RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol/guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene
  • methods of detecting a presence, absence, or level of a genotype or biomarker in the sample obtained from the subject involve detecting a nucleic acid sequence.
  • the nucleic acid sequence comprises deoxyribonucleic acid (DNA).
  • the nucleic acid sequence comprises a denatured DNA molecule or fragment thereof.
  • the nucleic acid sequence comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA.
  • the DNA is single -stranded DNA (ssDNA), double-stranded DNA, denaturing double -stranded DNA, synthetic DNA, and combinations thereof.
  • the circular DNA may be cleaved or fragmented.
  • the nucleic acid sequence comprises ribonucleic acid (RNA).
  • the nucleic acid sequence comprises fragmented RNA.
  • the nucleic acid sequence comprises partially degraded RNA.
  • the nucleic acid sequence comprises a microRNA or portion thereof.
  • the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri-miRNA, a mRNA, a pre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circular RNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), a pre-tRNA, a long non-coding RNA (IncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell-free RNA, an exosomal RNA, a vector-expressed RNA, an RNA transcript, a synthetic RNA, and combinations thereof.
  • miRNA microRNA
  • pre-miRNA pre-miRNA
  • a pri-miRNA a RNA
  • mRNA a pre-mRNA
  • a pri-miRNA a
  • the nucleic acid assayed comprises at least one SNP disclosed herein.
  • methods comprise assaying for at least two SNPs disclosed herein.
  • methods comprise assaying for at least three SNPs disclosed herein.
  • methods comprise assaying for at least four SNPs disclosed herein.
  • methods comprise assaying for all SNPs disclosed herein.
  • methods disclose detecting the presence of at least one SNP disclosed herein.
  • methods comprise detecting at least two SNPs disclosed herein.
  • methods comprise detecting at least three SNPs disclosed herein. Any two SNPs may be assayed for, or detected, simultaneously or sequentially.
  • the SNP assayed comprises rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs467640l, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621
  • the SNP is positioned within a sequence selected from SEQ ID NOS: 32-124.
  • the genotype detected using the methods described herein comprises rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G
  • the genotype detected comprises a SNP in linkage disequilibrium (LD) with one or more the above SNPs.
  • LD is determined by an r 2 value of at least about 0.80, about 0.85, about 0.90, about 0.95, or about 1.0.
  • the genotype comprises a risk allele provided in [brackets] within SEQ ID NO: 1-31 as shown in Table 30.
  • the genotype or biomarker is detected by subjecting a sample obtained from the subject to a nucleic acid-based detection assay.
  • the nucleic acid-based detection assay comprises quantitative polymerase chain reaction (qPCR), gel electrophoresis (including for e.g., Northern or Southern blot), immunochemistry, in situ
  • the sequencing technique comprises next generation sequencing.
  • FISH fluorescent in situ hybridization
  • cytochemistry cytochemistry
  • sequencing technique comprises next generation sequencing.
  • the methods involve a hybridization assay such as fluorogenic qPCR (e g., TaqManTM, SYBR green, SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin), which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acid probes comprising a detectable moiety or molecule that is specific to a target nucleic acid sequence.
  • a number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles.
  • the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles.
  • the probe may be a hydrolysable probe comprising a fluorophore and quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid.
  • the presence of a target nucleic acid is determined when the number of amplification cycles to reach a threshold value is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles.
  • hybridization may occur at standard hybridization temperatures, e.g., between about 35 °C and about 65 °C in a standard PCR buffer.
  • An additional exemplary nucleic acid-based detection assay comprises the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence.
  • the nucleic acid probe is specific to one or more genetic variants disclosed herein is used.
  • the nucleic acid probe specific to a SNP or SNV comprises a nucleic acid probe sequence sufficiently complementary to a risk or protective allele of interest, such that hybridization is specific to the risk or protective allele.
  • the nucleic acid probe specific to an indel comprises a nucleic acid probe sequence sufficiently complementary to an insertion of a nucleobase within a polynucleotide sequence flanking the insertion, such that hybridization is specific to the indel.
  • the nucleic acid probe specific to an indel comprises a probe sequence sufficiently complementary to a polynucleotide sequence flanking a deletion of a nucleobase within the polynucleotide sequence, such that hybridization is specific to the indel.
  • the nucleic acid probe specific to a biomarker comprises a nucleic acid probe sequence sufficiently complementary to the polynucleotide sequence of the biomarker.
  • the biomarker comprises a transcribed polynucleotide sequence (e.g., RNA, cDNA).
  • the nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length and sufficient to specifically hybridize under standard hybridization conditions to the target nucleic acid sequence.
  • the target nucleic acid sequence is immobilized on a solid surface and contacted with a probe, for example by running the isolated target nucleic acid sequence on an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane, such as nitrocellulose.
  • the probe(s) are immobilized on a solid surface, for example, in an Affymetrix gene chip array, and the probe(s) are contacted with the target nucleic acid sequence. Multiple alleles can be detected in individual reactions or in a single reaction (a“multiplex” assay).
  • the present disclosure provides exemplary probes that are hybridizable to a target nucleic acid sequence comprising a risk allele at rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608,
  • the present disclosure provides exemplary probes provided in SEQ ID NOS: 32-124.
  • the probe comprises at least about 10, at least about 15, at least about 20, at least about 25, at least about 30, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, from about 10 to about 50 nucleobases.
  • the probe comprises a sequence comprising no more than about 1, about 2, or about 3 nucleobase substitutions, insertions, or deletions from a nucleic acid selected from SEQ ID NOS: 1-124.
  • the term“probe” with regards to nucleic acids refers to any nucleic acid molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence.
  • probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a
  • the fluorescent label comprises a fluorophore.
  • the fluorophore is an aromatic or heteroaromatic compound.
  • the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxaazole, mdole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin.
  • Exemplary xanthene dyes include, e.g., fluorescein and rhodamine dyes.
  • Fluorescein and rhodamine dyes include, but are not limited to 6-carboxyfluorescein (FAM), 2'7'-dimethoxy-4'5'-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N'-tetramethyl-6- carboxyrhodamine (TAMRA), 6-carboxy-X -rhodamine (ROX).
  • FAM 6-carboxyfluorescein
  • JE 2'7'-dimethoxy-4'5'-dichloro-6-carboxyfluorescein
  • TET tetrachlorofluorescein
  • R6G 6-carboxyrhodamine
  • TAMRA N'-tetramethyl-6
  • Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position.
  • naphthylamino compounds include l-dimethylaminonaphthyl-5-sulfonate, l-anilino-8-naphthalene sulfonate and 2-p-toluidinyl-6-naphthalene sulfonate, 5-(2'-aminoethyl)aminonaphthalene-l -sulfonic acid (EDANS).
  • Exemplary coumarins include, e.g., 3-phenyl-7-isocyanatocoumarin; acridines, such as 9-isothiocyanatoacridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl) maleimide; cyanines, such as, e.g., indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3 -(-carboxy-pentyl)-3 '-ethyl-5,5 '-dimethyloxacarbocyanine (CyA); 1H, 5H, 11H, 15H- Xantheno[2,3, 4-ij: 5,6, 7-i'j , ]diquinolizin-18-ium, 9-[2 (or 4)-[[[6-[2,5-dioxo-l-pyrrol
  • a genotype or biomarker is detected by subjecting a biological sample obtained from the subject to a nucleic acid amplification assay.
  • the amplification assay comprises polymerase chain reaction (PCR), qPCR, self-sustained sequence replication, transcriptional amplification system, Q-Beta Replicase, rolling circle replication, or any suitable other nucleic acid amplification technique.
  • PCR polymerase chain reaction
  • qPCR self-sustained sequence replication
  • transcriptional amplification system transcriptional amplification system
  • Q-Beta Replicase rolling circle replication
  • rolling circle replication or any suitable other nucleic acid amplification technique.
  • a suitable nucleic acid amplification technique is configured to amplify a region of a nucleic acid sequence comprising one or more genetic risk variants disclosed herein.
  • the amplification assays requires primers.
  • the nucleic acid sequence for the genetic risk variants and/or genes known or provided herein is sufficient to enable one of skill in the art to select primers to amplify any portion of the gene or genetic variants.
  • a DNA sample suitable as a primer may be obtained, e.g., by polymerase chain reaction (PCR) amplification of genomic DNA, fragments of genomic DNA, fragments of genomic DNA ligated to adaptor sequences or cloned sequences.
  • PCR polymerase chain reaction
  • a person of skill in the art would utilize computer programs to design of primers with the desired specificity and optimal amplification properties, such as Oligo version 7.0 (National Biosciences). Controlled robotic systems are useful for isolating and amplifying nucleic acids and can be used.
  • Non-limiting examples of additional nucleic acid detection assays useful for the detection of a presence or absence of a genotype include restriction fragment length polymorphism (RFLP) analysis, a heteroduplex mobility assay (HMA), single strand conformational, polymorphism (SSCP), Denaturing gradient gel electrophoresis (DGGE), and RNAase mismatch techniques.
  • restriction fragment length polymorphism analysis is any method for distinguishing genetic polymorphisms using a restriction enzyme, which is an endonuclease that catalyzes the degradation of nucleic acid and recognizes a specific base sequence, generally a palindrome or inverted repeat.
  • HMA is useful for detecting the presence of a polymorphic sequence since a DNA duplex carrying a mismatch has reduced mobility in a polyacrylamide gel compared to the mobility of a perfectly base-paired duplex.
  • SSCP can be used to detect mutations based on differences in the secondary structure of single -strand DNA that produce an altered electrophoretic mobility upon non-denaturing gel electrophoresis. Polymorphic fragments are detected by comparison of the electrophoretic pattern of the test fragment to corresponding standard fragments containing known alleles.
  • double-stranded DNA is electrophoresed in a gel containing an increasing concentration of denaturant; double -stranded fragments made up of mismatched alleles have segments that melt more rapidly, causing such fragments to migrate differently as compared to perfectly complementary sequences.
  • detecting the biomarker or genotype of the subject comprises sequencing genetic material obtained from a biological sample from the subject.
  • Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g. , Sanger) sequencing, +S sequencing, or sequencing by synthesis.
  • Sequencing methods also include next- generation sequencing, e.g., modem sequencing technologies such as Illumina sequencing (e , Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next- generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.
  • a number of nucleotides that are sequenced are at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than 100000 nucleotides.
  • the number of nucleotides sequenced is in a range of about 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 100000 nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300 nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs2975780.
  • rs2975780 is associated with increased GPR35 expression.
  • rs2975780 is associated with increased GPR35 activity.
  • rs2975780 is associated with decreased GPR35 expression.
  • rs2975780 is associated with decreased GPR35 activity.
  • rs2975780 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs2975780 comprises SEQ ID NO: 9.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676396.
  • rs4676396 is associated with increased GPR35 expression.
  • rs4676396 is associated with increased GPR35 activity.
  • rs4676396 is associated with decreased GPR35 expression.
  • rs4676396 is associated with decreased GPR35 activity.
  • rs4676396 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs4676396 comprises SEQ ID NO: 10.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs6735672
  • rs6735672 is associated with increased GPR35 expression
  • rs6735672 is associated with increased GPR35 activity.
  • rs6735672 is associated with decreased GPR35 expression.
  • rs6735672 is associated with decreased GPR35 activity.
  • rs6735672 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs6735672 comprises SEQ ID NO: 11.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs34228697.
  • rs34228697 is associated with increased GPR35 expression.
  • rs34228697 is associated with increased GPR35 activity.
  • rs34228697 is associated with decreased GPR35 expression.
  • rs34228697 is associated with decreased GPR35 activity.
  • rs34228697 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs34228697 comprises SEQ ID NO: 12.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676401.
  • rs4676401 is associated with increased GPR35 expression.
  • rs4676401 is associated with increased GPR35 activity.
  • rs4676401 is associated with decreased GPR35 expression.
  • rs6735672 is associated with decreased GPR35 activity.
  • rs4676401 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs4676401 comprises SEQ ID NO: 13.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs2975786.
  • rs2975786 is associated with increased GPR35 expression.
  • rs2975786 is associated with increased GPR35 activity.
  • rs2975786 is associated with decreased GPR35 expression.
  • rs2975786 is associated with decreased GPR35 activity.
  • rs2975786 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs2975786 comprises SEQ ID NO: 14.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676346.
  • rs4676346 is associated with increased GPR35 expression.
  • rs4676346 is associated with increased GPR35 activity.
  • rs4676346 is associated with decreased GPR35 expression.
  • rs4676346 is associated with decreased GPR35 activity.
  • rs4676346 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs4676346 comprises SEQ ID NO: 15.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs6437356.
  • rs6437356 is associated with increased GPR35 expression.
  • rs6437356 is associated with increased GPR35 activity.
  • rs6437356 is associated with decreased GPR35 expression.
  • rs6437356 is associated with decreased GPR35 activity.
  • rs6437356 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs6437356 comprises SEQ ID NO: 16.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs6745185.
  • rs6745185 is associated with increased GPR35 expression.
  • rs6745185 is associated with increased GPR35 activity.
  • rs6745185 is associated with decreased GPR35 expression.
  • rs6745185 is associated with decreased GPR35 activity.
  • rs6745185 may have a risk allele of C in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs6745185 comprises SEQ ID NO: 17.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676407.
  • rs4676407 is associated with increased GPR35 expression.
  • rs4676407 is associated with increased GPR35 activity.
  • rs4676407 is associated with decreased GPR35 expression.
  • rs4676407 is associated with decreased GPR35 activity.
  • rs4676407 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35.
  • a non -limiting example of a sequence including rs4676407 comprises SEQ ID NO: 18.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs2953156.
  • rs2953156 is associated with increased GPR35 expression.
  • rs2953156 is associated with increased GPR35 activity.
  • rs2953156 is associated with decreased GPR35 expression.
  • rs2953156 is associated with decreased GPR35 activity.
  • rs2953156 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs2953156 comprises SEQ ID NO: 19.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs4335944.
  • rs4335944 is associated with increased GPR35 expression.
  • rs4335944 is associated with increased GPR35 activity.
  • rs4335944 is associated with decreased GPR35 expression.
  • rs4335944 is associated with decreased GPR35 activity.
  • rs4335944 may have a risk allele of C in a sense strand of a DNA molecule encoding GPR35
  • a non-limiting example of a sequence including rs4335944 comprises SEQ ID NO: 20 [00190]
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs73999973.
  • rs73999973 is associated with increased GPR35 expression.
  • rs73999973 is associated with increased GPR35 activity.
  • rs73999973 is associated with decreased GPR35 expression.
  • rs73999973 is associated with decreased GPR35 activity.
  • rs73999973 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs73999973 comprises SEQ ID NO: 21.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676410.
  • rs4676410 is associated with increased GPR35 expression.
  • rs4676410 is associated with increased GPR35 activity.
  • rs4676410 is associated with decreased GPR35 expression.
  • rs4676410 is associated with decreased GPR35 activity.
  • rs4676410 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs4676410 comprises SEQ ID NO: 22.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676405.
  • rs4676405 is associated with increased GPR35 expression.
  • rs4676405 is associated with increased GPR35 activity.
  • rs4676405 is associated with decreased GPR35 expression.
  • rs4676405 is associated with decreased GPR35 activity.
  • rs4676405 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs4676405 comprises SEQ ID NO: 23.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs2953154.
  • rs2953154 is associated with increased GPR35 expression.
  • rs2953154 is associated with increased GPR35 activity.
  • rs2953154 is associated with decreased GPR35 expression.
  • rs2953154 is associated with decreased GPR35 activity.
  • rs2953154 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs2953154 comprises SEQ ID NO: 24.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs6732874.
  • rs6732874 is associated with increased GPR35 expression.
  • rs6732874 is associated with increased GPR35 activity.
  • rs6732874 is associated with decreased GPR35 expression.
  • rs6732874 is associated with decreased GPR35 activity.
  • rs6732874 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs6732874 comprises SEQ ID NO: 25.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs55862430.
  • rs55862430 is associated with increased GPR35 expression.
  • rs55862430 is associated with increased GPR35 activity.
  • rs55862430 is associated with decreased GPR35 expression.
  • rs55862430 is associated with decreased GPR35 activity.
  • rs55862430 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs55862430 comprises SEQ ID NO: 26
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rsl2621598.
  • rsl2621598 is associated with increased GPR35 expression.
  • rsl2621598 is associated with increased GPR35 activity.
  • rsl2621598 is associated with decreased GPR35 expression.
  • rsl2621598 is associated with decreased GPR35 activity.
  • rsl2621598 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rsl2621598 comprises SEQ ID NO: 27.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs55919442.
  • rs55919442 is associated with increased GPR35 expression.
  • rs55919442 is associated with increased GPR35 activity.
  • rs55919442 is associated with decreased GPR35 expression.
  • rs55919442 is associated with decreased GPR35 activity.
  • rs55919442 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs55919442 comprises SEQ ID NO: 28.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs74991608.
  • rs74991608 is associated with increased GPR35 expression.
  • rs74991608 is associated with increased GPR35 activity.
  • rs74991608 is associated with decreased GPR35 expression.
  • rs74991608 is associated with decreased GPR35 activity.
  • rs74991608 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs74991608 comprises SEQ ID NO: 29.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs34826997.
  • rs34826997 is associated with increased GPR35 expression.
  • rs34826997 is associated with increased GPR35 activity.
  • rs34826997 is associated with decreased GPR35 expression.
  • rs34826997 is associated with decreased GPR35 activity.
  • rs34826997 may have a risk allele of T in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs34826997 comprises SEQ ID NO: 30.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs6437364.
  • rs6437364 is associated with increased GPR35 expression.
  • rs6437364 is associated with increased GPR35 activity.
  • rs6437364 is associated with decreased GPR35 expression.
  • rs6437364 is associated with decreased GPR35 activity.
  • rs6437364 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs6437364 comprises SEQ ID NO: 31.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rsl 13435444.
  • rsl 13435444 is associated with increased GPR35 expression.
  • rsl 13435444 is associated with increased GPR35 activity.
  • rsl 13435444 is associated with decreased GPR35 expression.
  • rsl 13435444 is associated with decreased GPR35 activity rsl 13435444 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rsl 13435444 comprises SEQ ID NO: 1.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs3749171.
  • rs3749171 is associated with increased GPR35 expression.
  • rs3749171 is associated with increased GPR35 activity.
  • rs3749171 is associated with decreased GPR35 expression.
  • rs3749171 is associated with decreased GPR35 activity.
  • rs3749171 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs3749171 comprises SEQ ID NO: 2.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676406.
  • rs4676406 is associated with increased GPR35 expression.
  • rs4676406 is associated with increased GPR35 activity.
  • rs4676406 is associated with decreased GPR35 expression.
  • rs4676406 is associated with decreased GPR35 activity.
  • rs4676406 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs4676406 comprises SEQ ID NO: 3.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676399.
  • rs4676399 is associated with increased GPR35 expression.
  • rs4676399 is associated with increased GPR35 activity.
  • rs4676399 is associated with decreased GPR35 expression.
  • rs4676399 is associated with decreased GPR35 activity.
  • rs4676399 may have a risk allele of C in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs4676399 comprises SEQ ID NO: 4.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs2975782.
  • rs2975782 is associated with increased GPR35 expression.
  • rs2975782 is associated with increased GPR35 activity.
  • rs2975782 is associated with decreased GPR35 expression.
  • rs2975782 is associated with decreased GPR35 activity.
  • rs2975782 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs2975782 comprises SEQ ID NO: 5.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs3749172.
  • rs3749172 is associated with increased GPR35 expression.
  • rs3749172 is associated with increased GPR35 activity.
  • rs3749172 is associated with decreased GPR35 expression.
  • rs3749172 is associated with decreased GPR35 activity.
  • rs3749172 may have a risk allele of C in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs3749172 comprises SEQ ID NO: 6
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs79844648.
  • rs79844648 is associated with increased GPR35 expression.
  • rs79844648 is associated with increased GPR35 activity.
  • rs79844648 is associated with decreased GPR35 expression.
  • rs79844648 is associated with decreased GPR35 activity.
  • rs79844648 may have a risk allele of G in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs79844648 comprises SEQ ID NO: 7.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is rs4676402.
  • rs4676402 is associated with increased GPR35 expression.
  • rs4676402 is associated with increased GPR35 activity.
  • rs4676402 is associated with decreased GPR35 expression.
  • rs4676402 is associated with decreased GPR35 activity.
  • rs4676402 may have a risk allele of A in a sense strand of a DNA molecule encoding GPR35.
  • a non-limiting example of a sequence including rs4676402 comprises SEQ ID NO: 8.
  • methods comprise assaying for or detecting a SNP, wherein the SNP is selected from Table 1.
  • the SNP is associated with increased GPR35 expression.
  • the SNP is associated with increased GPR35 activity.
  • the SNP is associated with decreased GPR35 expression.
  • the SNP is associated with decreased GPR35 activity.
  • methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs comprise two SNPs selected from Table 1.
  • a SNP is positioned within a sequence selected from SEQ ID NOS: 32-124.
  • the two SNPs may be rsl 13435444 and rs3749171.
  • the two SNPs may be rsl 13435444 and rs4676406.
  • the two SNPs may be rsl 13435444 and rs4676399.
  • the two SNPs may be rsl 13435444 and rs2975782.
  • the two SNPs may be rsl 13435444 and rs3749172.
  • the two SNPs may be rsl 13435444 and rs79844648.
  • the two SNPs may be rsl 13435444 and rs4676402.
  • the two SNPs may be rsl 13435444 and rs2975780.
  • the two SNPs may be rsl 13435444 and rs4676396.
  • the two SNPs may be rsl 13435444 and rs6735672.
  • the two SNPs may be rsl 13435444 and rs34228697.
  • the two SNPs may be rsl 13435444 and rs4676401.
  • the two SNPs may be rsl 13435444 and rs2975786.
  • the two SNPs may be rsl 13435444 and rs4676346.
  • the two SNPs may be rsl 13435444 and rs6437356.
  • the two SNPs may be rsl 13435444 and rs6745185.
  • the two SNPs may be rsl 13435444 and rs4676407.
  • the two SNPs may be rsl 13435444 and rs2953156.
  • the two SNPs may be rsl 13435444 and rs4335944.
  • the two SNPs may be rsl 13435444 and rs73999973.
  • the two SNPs may be rsl 13435444 and rs4676410.
  • the two SNPs may be rsl 13435444 and rs4676405.
  • the two SNPs may be rsl 13435444 and rs2953154.
  • the two SNPs may be rsl 13435444 and rs6732874.
  • the two SNPs may be rsl 13435444 and rs55862430.
  • the two SNPs may be rsl 13435444 and rsl2621598.
  • the two SNPs may be rsl 13435444 and rs55919442.
  • the two SNPs may be rsl 13435444 and rs74991608.
  • the two SNPs may be rsl 13435444 and rs34826997.
  • the two SNPs may be rsl 13435444 and rs6437364.
  • methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs3749171and rs4676406.
  • the two SNPs may be rs3749171 and rs4676399.
  • the two SNPs may be rs3749171 and rs2975782.
  • the two SNPs may be rs3749171 and rs3749172.
  • the two SNPs may be rs3749171 and rs79844648.
  • the two SNPs may be rs3749171 and rs4676402.
  • the two SNPs may be rs3749171 and rs2975780.
  • the two SNPs may be rs3749171 and rs4676396.
  • the two SNPs may be rs3749171 and rs6735672.
  • the two SNPs may be rs3749171 and rs34228697.
  • the two SNPs may be rs3749171 and rs4676401.
  • the two SNPs may be rs3749171 and rs2975786.
  • the two SNPs may be rs3749171 and rs4676346.
  • the two SNPs may be rs3749171 and rs6437356.
  • the two SNPs may be rs3749171 and rs6745185.
  • the two SNPs may be rs3749171and and rs4676407.
  • the two SNPs may be rs3749171 and rs2953156.
  • the two SNPs may be rs3749171 and rs4335944.
  • the two SNPs may be rs3749171 and rs73999973.
  • the two SNPs may be rs3749171 and rs4676410.
  • the two SNPs may be rs3749171and and rs4676405.
  • the two SNPs may be rs3749171 and rs2953154.
  • the two SNPs may be rs3749171 and rs6732874.
  • the two SNPs may be rs3749171 and rs55862430.
  • the two SNPs may be rs3749171 and rsl2621598.
  • the two SNPs may be rs3749171and and rs55919442.
  • the two SNPs may be rs3749171 and rs74991608.
  • the two SNPs may be rs3749171 and rs34826997.
  • the two SNPs may be rs3749171 and rs6437364.
  • methods comprise detecting at least two SNPs in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs4676406 and rs4676399.
  • the two SNPs may be rs4676406 and rs2975782.
  • the two SNPs may be rs4676406 and rs3749172
  • the two SNPs may be rs4676406 and rs79844648.
  • the two SNPs may be rs4676406 and rs4676402
  • the two SNPs may be rs4676406 and rs2975780
  • the two SNPs may be rs4676406 and rs4676396.
  • the two SNPs may be rs4676406 and rs6735672.
  • the two SNPs may be rs4676406 and rs34228697.
  • the two SNPs may be rs4676406 and rs4676401.
  • the two SNPs may be rs4676406 and rs2975786.
  • the two SNPs may be rs4676406 and rs4676346.
  • the two SNPs may be rs4676406 and rs6437356.
  • the two SNPs may be rs4676406 and rs6745185.
  • the two SNPs may be rs4676406 and rs4676407
  • the two SNPs may be rs4676406 and rs2953156
  • the two SNPs may be rs4676406 and rs4335944.
  • the two SNPs may be rs4676406 and rs73999973.
  • the two SNPs may be rs4676406 and rs4676410.
  • the two SNPs may be rs4676406 and rs4676405.
  • the two SNPs may be rs4676406 and rs2953154.
  • the two SNPs may be rs4676406 and rs6732874.
  • the two SNPs may be rs4676406 and rs55862430.
  • the two SNPs may be rs4676406 and rsl2621598.
  • the two SNPs may be rs4676406 and rs55919442.
  • the two SNPs may be rs4676406 and rs74991608.
  • the two SNPs may be rs4676406 and rs34826997.
  • the two SNPs may be rs4676406 and rs6437364.
  • methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs4676399 and rs2975782.
  • the two SNPs may be rs4676399 and rs3749172.
  • the two SNPs may be rs4676399 and rs79844648.
  • the two SNPs may be rs4676399 and rs4676402.
  • the two SNPs may be rs4676399 and rs2975780.
  • the two SNPs may be rs4676399 and rs4676396.
  • the two SNPs may be rs4676399 and rs6735672.
  • the two SNPs may be rs4676399 and rs34228697.
  • the two SNPs may be rs4676399 and rs4676401.
  • the two SNPs may be rs4676399 and rs2975786.
  • the two SNPs may be rs4676399 and rs4676346.
  • the two SNPs may be rs4676399 and rs6437356.
  • the two SNPs may be rs4676399 and rs6745185.
  • the two SNPs may be rs4676399 and rs4676407.
  • the two SNPs may be rs4676399 and rs2953156.
  • the two SNPs may be rs4676399 and rs4335944.
  • the two SNPs may be rs4676399 and rs73999973.
  • the two SNPs may be rs4676399 and rs4676410.
  • the two SNPs may be rs4676399 and rs4676405.
  • the two SNPs may be rs4676399 and rs2953154.
  • the two SNPs may be rs4676399 and rs6732874.
  • the two SNPs may be rs4676399 and rs55862430.
  • the two SNPs may be rs4676399 and rsl2621598.
  • the two SNPs may be rs4676399 and rs55919442.
  • the two SNPs may be rs4676399 and rs74991608.
  • the two SNPs may be rs4676399 and rs34826997.
  • the two SNPs may be rs4676399 and rs6437364.
  • methods comprise detecting at least two SNPs in a gene encoding GPR35. In some instances, methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs2975782 and rs3749172.
  • the two SNPs may be rs2975782 and rs79844648.
  • the two SNPs may be rs2975782 and rs4676402.
  • the two SNPs may be rs2975782 and rs2975780.
  • the two SNPs may be rs2975782 and rs4676396.
  • the two SNPs may be rs2975782 and rs6735672.
  • the two SNPs may be rs2975782 and rs34228697.
  • the two SNPs may be rs2975782 and rs4676401.
  • the two SNPs may be rs2975782 and rs2975786.
  • the two SNPs may be rs2975782 and rs4676346
  • the two SNPs may be rs2975782 and rs6437356.
  • the two SNPs may be rs2975782 and rs6745185
  • the two SNPs may be rs2975782 and rs4676407.
  • the two SNPs may be rs2975782 and rs2953156.
  • the two SNPs may be rs2975782 and rs4335944.
  • the two SNPs may be rs2975782 and rs73999973.
  • the two SNPs may be rs2975782 and rs4676410.
  • the two SNPs may be rs2975782 and rs4676405.
  • the two SNPs may be rs2975782 and rs2953154.
  • the two SNPs may be rs2975782 and rs6732874.
  • the two SNPs may be rs2975782 and rs55862430.
  • the two SNPs may be rs2975782 and rsl2621598.
  • the two SNPs may be rs2975782 and rs55919442.
  • the two SNPs may be rs2975782 and rs74991608.
  • the two SNPs may be rs2975782 and rs34826997.
  • the two SNPs may be rs2975782 and rs6437364.
  • methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs3749172 and rs79844648.
  • the two SNPs may be rs3749172 and rs4676402.
  • the two SNPs may be rs3749172 and rs2975780.
  • the two SNPs may be rs3749172 and rs4676396.
  • the two SNPs may be rs3749172 and rs6735672.
  • the two SNPs may be rs3749172 and rs34228697.
  • the two SNPs may be rs3749172 and rs4676401.
  • the two SNPs may be rs3749172 and rs2975786.
  • the two SNPs may be rs3749172 and rs4676346.
  • the two SNPs may be rs3749172 and rs6437356.
  • the two SNPs may be rs3749172 and rs6745185.
  • the two SNPs may be rs3749172 and rs4676407.
  • the two SNPs may be rs3749172 and rs2953156.
  • the two SNPs may be rs3749172 and rs4335944.
  • the two SNPs may be rs3749172 and rs73999973.
  • the two SNPs may be rs3749172 and rs4676410.
  • the two SNPs may be rs3749172 and rs4676405.
  • the two SNPs may be rs3749172 and rs2953154.
  • the two SNPs may be rs3749172 and rs6732874.
  • the two SNPs may be rs3749172 and rs55862430.
  • the two SNPs may be rs3749172 and rsl2621598.
  • the two SNPs may be rs3749172 and rs55919442.
  • the two SNPs may be rs3749172 and rs74991608.
  • the two SNPs may be rs3749172 and rs34826997.
  • the two SNPs may be rs3749172 and rs6437364.
  • methods comprise detecting at least two SNPs in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs79844648 and rs4676402.
  • the two SNPs may be rs79844648 and rs2975780.
  • the two SNPs may be rs79844648 and rs4676396.
  • the two SNPs may be rs79844648 and rs6735672.
  • the two SNPs may be rs79844648 and rs34228697.
  • the two SNPs may be rs79844648 and rs4676401.
  • the two SNPs may be rs79844648 and rs2975786.
  • the two SNPs may be rs79844648 and rs4676346.
  • the two SNPs may be rs79844648 and rs6437356.
  • the two SNPs may be rs79844648 and rs6745185.
  • the two SNPs may be rs79844648 and rs4676407.
  • the two SNPs may be rs79844648 and rs2953156.
  • the two SNPs may be rs79844648 and rs4335944.
  • the two SNPs may be rs79844648 and rs73999973.
  • the two SNPs may be rs79844648 and rs4676410.
  • the two SNPs may be rs79844648 and rs4676405.
  • the two SNPs may be rs79844648 and rs2953154.
  • the two SNPs may be rs79844648 and rs6732874.
  • the two SNPs may be rs79844648 and rs55862430.
  • the two SNPs may be rs79844648 and rsl2621598.
  • the two SNPs may be rs79844648 and rs55919442.
  • the two SNPs may be rs79844648 and rs74991608.
  • the two SNPs may be rs79844648 and rs34826997.
  • the two SNPs may be rs79844648 and rs6437364.
  • methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs4676402 and rs2975780.
  • the two SNPs may be rs4676402 and rs4676396.
  • the two SNPs may be rs4676402 and rs6735672.
  • the two SNPs may be rs4676402 and rs34228697.
  • the two SNPs may be rs4676402 and rs4676401.
  • the two SNPs may be rs4676402 and rs2975786.
  • the two SNPs may be rs4676402 and rs4676346.
  • the two SNPs may be rs4676402 and rs6437356.
  • the two SNPs may be rs4676402 and rs6745185.
  • the two SNPs may be rs4676402 and rs4676407.
  • the two SNPs may be rs4676402 and rs2953156.
  • the two SNPs may be rs4676402 and rs4335944.
  • the two SNPs may be rs4676402 and rs73999973.
  • the two SNPs may be rs4676402 and rs4676410.
  • the two SNPs may be rs4676402 and rs4676405.
  • the two SNPs may be rs4676402 and rs2953154.
  • the two SNPs may be rs4676402 and rs6732874.
  • the two SNPs may be rs4676402 and rs55862430.
  • the two SNPs may be rs4676402 and rsl2621598.
  • the two SNPs may be rs4676402 and rs55919442.
  • the two SNPs may be rs4676402 and rs74991608.
  • the two SNPs may be rs4676402 and rs34826997.
  • the two SNPs may be rs4676402 and rs6437364.
  • methods comprise detecting at least two SNPs in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs2975780 and rs4676396.
  • the two SNPs may be rs2975780 and rs6735672.
  • the two SNPs may be rs2975780 and rs34228697.
  • the two SNPs may be rs2975780 and rs4676401.
  • the two SNPs may be rs2975780 and rs2975786.
  • the two SNPs may be rs2975780 and rs4676346.
  • the two SNPs may be rs2975780 and rs6437356.
  • the two SNPs may be rs2975780 and rs6745185.
  • the two SNPs may be rs2975780 and rs4676407.
  • the two SNPs may be rs2975780 and rs2953156.
  • the two SNPs may be rs2975780 and rs4335944.
  • the two SNPs may be rs2975780 and rs73999973.
  • the two SNPs may be rs2975780 and rs4676410.
  • the two SNPs may be rs2975780 and rs4676405.
  • the two SNPs may be rs2975780 and rs2953154.
  • the two SNPs may be rs2975780 and rs6732874.
  • the two SNPs may be rs2975780 and rs55862430.
  • the two SNPs may be rs2975780 and rsl2621598.
  • the two SNPs may be rs2975780 and rs55919442.
  • the two SNPs may be rs2975780 and rs74991608.
  • the two SNPs may be rs2975780 and rs34826997.
  • the two SNPs may be rs2975780 and rs6437364.
  • the two SNPs may be rs4676396 and rs6735672.
  • the two SNPs may be rs4676396 and rs34228697.
  • the two SNPs may be rs4676396 and rs4676401.
  • the two SNPs may be rs4676396 and rs2975786.
  • the two SNPs may be rs4676396 and rs4676346.
  • the two SNPs may be rs4676396 and rs6437356.
  • the two SNPs may be rs4676396 and rs6745185.
  • the two SNPs may be rs4676396 and rs4676407.
  • the two SNPs may be rs4676396 and rs2953156
  • the two SNPs may be rs4676396 and rs4335944
  • the two SNPs may be rs4676396 and rs73999973.
  • the two SNPs may be rs4676396 and rs4676410.
  • the two SNPs may be rs4676396 and rs4676405.
  • the two SNPs may be rs4676396 and rs2953154.
  • the two SNPs may be rs4676396 and rs6732874.
  • the two SNPs may be rs4676396 and rs55862430.
  • the two SNPs may be rs4676396 and rsl2621598.
  • the two SNPs may be rs4676396 and rs55919442.
  • the two SNPs may be rs4676396 and rs74991608.
  • the two SNPs may be rs4676396 and rs34826997.
  • the two SNPs may be rs4676396 and rs6437364.
  • methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs6735672 and rs34228697.
  • the two SNPs may be rs6735672 and rs4676401.
  • the two SNPs may be rs6735672 and rs2975786.
  • the two SNPs may be rs6735672 and rs4676346.
  • the two SNPs may be rs6735672 and rs4676346.
  • SNPs may be rs6735672 and rs6437356.
  • the two SNPs may be rs6735672 and rs6745185.
  • the two SNPs may be rs6735672 and rs6745185.
  • SNPs may be rs6735672 and rs4676407.
  • the two SNPs may be rs6735672 and rs2953156.
  • the two SNPs may be rs6735672 and rs2953156.
  • SNPs may be rs6735672 and rs4335944.
  • the two SNPs may be rs6735672 and rs73999973.
  • the two SNPs may be rs6735672 and rs4676410.
  • the two SNPs may be rs6735672 and rs4676405.
  • SNPs may be rs6735672 and rs2953154.
  • the two SNPs may be rs6735672 and rs6732874.
  • the two SNPs may be rs6735672 and rs6732874.
  • SNPs may be rs6735672 and rs55862430.
  • the two SNPs may be rs6735672 and rsl2621598.
  • the two SNPs may be rs6735672 and rs55919442.
  • the two SNPs may be rs6735672 and rs74991608.
  • the two SNPs may be rs6735672 and rs34826997.
  • the two SNPs may be rs6735672 and rs6437364.
  • the two SNPs may be rs34228697 and rs4676401.
  • the two SNPs may be rs34228697 and rs2975786.
  • the two SNPs may be rs34228697 and rs4676346.
  • the two SNPs may be rs34228697 and rs6437356.
  • the two SNPs may be rs34228697 and rs6745185.
  • the two SNPs may be rs34228697 and rs4676407.
  • the two SNPs may be rs34228697 and rs2953156.
  • the two SNPs may be rs34228697 and rs4335944.
  • the two SNPs may be rs34228697 and rs73999973.
  • the two SNPs may be rs34228697 and rs4676410.
  • the two SNPs may be rs34228697 and rs4676405.
  • the two SNPs may be rs34228697 and rs2953154.
  • the two SNPs may be rs34228697 and rs6732874.
  • the two SNPs may be rs34228697 and rs55862430.
  • the two SNPs may be rs34228697 and rs 12621598.
  • the two SNPs may be rs34228697 and rs55919442.
  • the two SNPs may be rs34228697 and rs74991608.
  • the two SNPs may be rs34228697 and rs34826997.
  • the two SNPs may be rs34228697 and rs6437364.
  • methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs4676401 and rs2975786.
  • the two SNPs may be rs4676401 and rs4676346.
  • the two SNPs may be rs4676401 and rs6437356.
  • the two SNPs may be rs4676401 and rs6745185.
  • the two SNPs may be rs4676401 and rs4676407.
  • the two SNPs may be rs4676401 and rs2953156.
  • the two SNPs may be rs4676401 and rs4335944.
  • the two SNPs may be rs4676401 and rs73999973.
  • the two SNPs may be rs4676401 and rs4676410.
  • the two SNPs may be rs4676401 and rs4676405.
  • the two SNPs may be rs4676401 and rs2953154.
  • the two SNPs may be rs4676401 and rs6732874.
  • the two SNPs may be rs4676401 and rs55862430.
  • the two SNPs may be rs4676401 and rsl2621598.
  • the two SNPs may be rs4676401 and rs55919442.
  • the two SNPs may be rs4676401 and rs74991608.
  • the two SNPs may be rs4676401 and rs34826997.
  • the two SNPs may be rs4676401 and rs6437364.
  • the two SNPs may be rs2975786 and rs4676346.
  • the two SNPs may be rs2975786 and rs6437356.
  • the two SNPs may be rs2975786 and rs6745185.
  • the two SNPs may be rs2975786 and rs4676407.
  • the two SNPs may be rs2975786 and rs2953156.
  • the two SNPs may be rs2975786 and rs4335944.
  • the two SNPs may be rs2975786 and rs73999973.
  • the two SNPs may be rs2975786 and rs46764l0.
  • the two SNPs may be rs2975786 and rs4676405.
  • the two SNPs may be rs2975786 and rs2953154.
  • the two SNPs may be rs2975786 and rs6732874.
  • the two SNPs may be rs2975786 and rs55862430.
  • the two SNPs may be rs2975786 and rsl2621598.
  • the two SNPs may be rs2975786 and rs55919442.
  • the two SNPs may be rs2975786 and rs74991608.
  • the two SNPs may be rs2975786 and rs34826997.
  • the two SNPs may be rs2975786 and rs6437364.
  • methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs4676346 and rs6437356.
  • the two SNPs may be rs4676346 and rs6745185.
  • the two SNPs may be rs4676346 and rs4676407.
  • the two SNPs may be rs4676346 and rs2953156.
  • the two SNPs may be rs4676346 and rs4335944.
  • the two SNPs may be rs4676346 and rs73999973.
  • the two SNPs may be rs4676346 and rs4676410.
  • the two SNPs may be rs4676346 and rs4676405.
  • the two SNPs may be rs4676346 and rs2953154.
  • the two SNPs may be rs4676346 and rs6732874.
  • the two SNPs may be rs4676346 and rs55862430.
  • the two SNPs may be rs4676346 and rsl2621598.
  • the two SNPs may be rs4676346 and rs55919442.
  • the two SNPs may be rs4676346 and rs74991608.
  • the two SNPs may be rs4676346 and rs34826997.
  • the two SNPs may be rs4676346 and rs6437364.
  • the two SNPs may be rs6437356 and rs6745185.
  • the two SNPs may be rs6437356 and rs4676407.
  • the two SNPs may be rs6437356 and rs2953156.
  • the two SNPs may be rs6437356 and rs4335944.
  • the two SNPs may be rs6437356 and rs73999973.
  • the two SNPs may be rs6437356 and rs4676410.
  • the two SNPs may be rs6437356 and rs4676405.
  • the two SNPs may be rs6437356 and rs2953154.
  • the two SNPs may be rs6437356 and rs6732874.
  • the two SNPs may be rs6437356 and rs55862430.
  • the two SNPs may be rs6437356 and rsl2621598.
  • the two SNPs may be rs6437356 and rs55919442.
  • the two SNPs may be rs6437356 and rs74991608.
  • the two SNPs may be rs6437356 and rs34826997.
  • the two SNPs may be rs6437356 and rs6437364.
  • the two SNPs may be rs6745185 and rs4676407.
  • the two SNPs may be rs6745185 and rs2953156.
  • the two SNPs may be rs6745185 and rs4335944.
  • the two SNPs may be rs6745185 and rs73999973.
  • the two SNPs may be rs6745185 and rs4676410.
  • the two SNPs may be rs6745185 and rs4676405.
  • the two SNPs may be rs6745185 and rs2953154.
  • the two SNPs may be rs6745185 and rs6732874.
  • the two SNPs may be rs6745185 and rs55862430.
  • the two SNPs may be rs6745185 and rsl2621598.
  • the two SNPs may be rs6745185 and rs55919442.
  • the two SNPs may be rs6745185 and rs74991608.
  • the two SNPs may be rs674 185 and rs34826997.
  • the two SNPs may be rs6745185 and rs6437364.
  • methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs4676407 and rs2953156.
  • the two SNPs may be rs4676407 and rs4335944.
  • the two SNPs may be rs4676407 and rs73999973.
  • the two SNPs may be rs4676407 and rs4676410.
  • the two SNPs may be rs4676407 and rs4676405.
  • the two SNPs may be rs4676407 and rs2953154.
  • the two SNPs may be rs4676407 and rs6732874.
  • the two SNPs may be rs4676407 and rs55862430.
  • the two SNPs may be rs4676407 and rsl2621598.
  • the two SNPs may be rs4676407 and rs55919442.
  • the two SNPs may be rs4676407 and rs74991608.
  • the two SNPs may be rs4676407 and rs34826997.
  • the two SNPs may be rs4676407 and rs6437364.
  • the two SNPs may be rs2953156 and rs4335944.
  • the two SNPs may be rs2953156 and rs73999973.
  • the two SNPs may be rs2953156 and rs4676410.
  • the two SNPs may be rs2953156 and rs4676405.
  • the two SNPs may be rs2953156 and rs2953154.
  • the two SNPs may be rs2953156 and rs6732874.
  • the two SNPs may be rs2953156 and rs55862430.
  • the two SNPs may be rs2953156 and rsl2621598.
  • the two SNPs may be rs2953156 and rs55919442.
  • the two SNPs may be rs2953156 and rs74991608.
  • the two SNPs may be rs2953156 and rs34826997.
  • the two SNPs may be rs2953156 and rs6437364.
  • the two SNPs may be rs4335944 and rs73999973.
  • the two SNPs may be rs4335944 and rs4676410.
  • the two SNPs may be rs4335944 and rs4676405.
  • the two SNPs may be rs4335944 and rs2953154.
  • the two SNPs may be rs4335944 and rs6732874.
  • the two SNPs may be rs4335944 and rs55862430.
  • the two SNPs may be rs4335944 and rsl2621598.
  • the two SNPs may be rs4335944 and rs55919442.
  • the two SNPs may be rs4335944 and rs74991608.
  • the two SNPs may be rs4335944 and rs34826997.
  • the two SNPs may be rs4335944 and rs6437364.
  • methods comprise detecting at least two SNPs in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs73999973 and rs4676410.
  • the two SNPs may be rs73999973 and rs4676405.
  • the two SNPs may be rs73999973 and rs2953154.
  • the two SNPs may be rs73999973 and rs6732874.
  • the two SNPs may be rs73999973 and rs55862430.
  • the two SNPs may be rs73999973 and rsl2621598.
  • the two SNPs may be rs73999973 and rs55919442.
  • the two SNPs may be rs73999973 and rs74991608.
  • the two SNPs may be rs73999973 and rs34826997.
  • the two SNPs may be rs73999973 and rs6437364.
  • the two SNPs may be rs4676410 and rs4676405.
  • the two SNPs may be rs4676410 and rs2953154.
  • the two SNPs may be rs4676410 and rs6732874.
  • the two SNPs may be rs4676410 and rs55862430.
  • the two SNPs may be rs4676410 and rsl2621598.
  • the two SNPs may be rs4676410 and rs55919442.
  • the two SNPs may be rs4676410 and rs74991608.
  • the two SNPs may be rs4676410 and rs34826997.
  • the two SNPs may be rs4676410 and rs6437364.
  • the two SNPs may be rs4676405 and rs2953154
  • the two SNPs may be rs4676405 and rs6732874.
  • the two SNPs may be rs4676405 and rs55862430.
  • the two SNPs may be rs4676405 and rsl2621598.
  • the two SNPs may be rs4676405 and rs55919442.
  • the two SNPs may be rs4676405 and rs74991608.
  • the two SNPs may be rs4676405 and rs34826997.
  • the two SNPs may be rs4676405 and rs6437364.
  • methods comprise detecting at least two single nucleotide polymorphisms (SNPs) in a gene encoding GPR35.
  • methods comprise administering a therapeutic agent disclosed herein to a subject having at least two SNPs in a gene encoding GPR35.
  • the two SNPs may be rs2953154 and rs6732874.
  • the two SNPs may be rs2953154 and rs55862430.
  • the two SNPs may be rs2953154 and rsl2621598.
  • the two SNPs may be rs2953154 and rs55919442.
  • SNPs may be rs2953154 and rs74991608.
  • the two SNPs may be rs2953154 and rs34826997.
  • the two SNPs may be rs2953154 and rs34826997.
  • SNPs may be rs2953154 and rs6437364.
  • the two SNPs may be rs6732874 and rs55862430.
  • the two SNPs may be rs6732874 and rsl2621598.
  • the two SNPs may be rs6732874 and rs55919442.
  • SNPs may be rs6732874 and rs74991608.
  • the two SNPs may be rs6732874 and rs34826997.
  • the two SNPs may be rs6732874 and rs34826997.
  • SNPs may be rs6732874and rs6437364.
  • the two SNPs may be rs55862430 and rsl2621598.
  • the two SNPs may be rs55862430 and rs55919442.
  • the two SNPs may be rs55862430 and rs74991608.
  • the two SNPs may be rs55862430 and rs34826997.
  • the two SNPs may be rs55862430 and rs6437364.
  • the two SNPs may be rsl2621598 and rs55919442.
  • the two SNPs may be rsl2621598 and rs74991608.
  • the two SNPs may be rsl2621598 and rs34826997.
  • the two SNPs may be rsl2621598 and rs6437364.
  • the two SNPs may be rs55919442 and rs74991608.
  • the two SNPs may be rs55919442 and rs6437364.
  • the two SNPs may be rs74991608 and rs34826997.
  • the two SNPs may be rs74991608 and rs6437364.
  • the two SNPs may be rs34826997 and rs6437364.
  • methods of detecting a presence, absence, or level of a target protein (e.g., biomarker) in the sample obtained from the subject involve detecting protein activity or expression.
  • a target protein may be detected by use of an antibody-based assay, where an antibody specific to the target protein is utilized.
  • antibody-based detection methods utilize an antibody that binds to any region of target protein.
  • An exemplary method of analysis comprises performing an enzyme-linked immunosorbent assay (ELISA).
  • the ELISA assay may be a sandwich ELISA or a direct ELISA.
  • Another exemplary method of analysis comprises a single molecule array, e.g., Simoa.
  • Other exemplary methods of detection include immunohistochemistry and lateral flow assay.
  • Additional exemplary methods for detecting target protein include, but are not limited to, gel electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, and the like, or various immunological methods such as fluid or gel precipitation reactions, immunodiffusion (single or double), Immunoelectrophoresis, radioimmunoassay (RIA), immunofluorescent assays, and Western blotting.
  • antibodies, or antibody fragments are used in methods such as Western blots or immunofluorescence techniques to detect the expressed proteins
  • the antibody or protein can be immobilized on a solid support for Western blots and immunofluorescence techniques.
  • Suitable solid phase supports or carriers include any support capable of binding an antigen or an antibody.
  • Exemplary supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.
  • a target protein may be detected by detecting binding between the target protein and a binding partner of the target protein.
  • the target protein comprises GPR35, or another protein involved in the GPR35.
  • Exemplary methods of analysis of protein-protein binding comprise performing an assay in vivo or in vitro, or ex vivo.
  • the method of analysis comprises an assay such as a co-immunoprecipitation (co-IP), pull-down, crosslinking protein interaction analysis, labeled transfer protein interaction analysis, or Far-western blot analysis, FRET based assay, including, for example FRET-FLIM, a yeast two-hybrid assay, BiFC, or split luciferase assay.
  • co-IP co-immunoprecipitation
  • FRET based assay including, for example FRET-FLIM, a yeast two-hybrid assay, BiFC, or split luciferase assay.
  • the serological marker may be a nucleic acid.
  • the nucleic acid may comprise DNA.
  • the nucleic acid may comprise RNA.
  • the nucleic acid may be a cell-free nucleic acid.
  • the marker may be a protein.
  • the protein may also be referred to herein as a“peptide.”
  • the protein may be a human protein.
  • the protein may be a non-human protein.
  • the protein may be an antibody or antibody fragment.
  • the antibodies comprises immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin E (IgE), or immunoglobulin M (IgM), immunoglobulin D (IgD), or a combination thereof.
  • the antibody or antibody fragment may bind an antigen, wherein the antigen is a bacterial particle.
  • the antibody or antibody fragment may bind an antigen, wherein the antigen is a yeast particle.
  • the antibody or antibody fragment may bind an antigen, wherein the antigen is a viral particle.
  • the term,“particle,” may refer to a nucleic acid, peptide or other cellular component.
  • the antibody or antibody fragment may bind an antigen on a cell of the subject.
  • the protein may be an ssAi-Saccharomyces cerevisiae antibody (ASCA), an anti-neutrophil cytoplasmic antibody (ANCA), or an E.coli outer membrane porin protein C (OmpC).
  • ASCA ssAi-Saccharomyces cerevisiae antibody
  • ANCA anti-neutrophil cytoplasmic antibody
  • OmpC E.coli outer membrane porin protein C
  • the presence or the level of the one or more serological markers is detected using an enzyme-linked immunosorbent assay (ELISA), a single molecule array (Simoa), immunohistochemistry, internal transcribed spacer (ITS) sequencing, or any combination thereof.
  • ELISA enzyme-linked immunosorbent assay
  • the ELISA is a fixed leukocyte ELISA.
  • the ELISA is a fixed neutrophil ELISA.
  • a fixed leukocyte or neutrophil ELISA may be useful for the detection of certain serological markers, such as those described in Saxon et al ., A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease, J Allergy Clin. Immuno. 86:2; 202-210 (August 1990).
  • ELISA units are used to measure positivity of a presence or level of a serological marker (e.g.,
  • the standard comprises pooled sera obtained from well-characterized patient population (e g., diagnosed with the same disease or condition the subject has, or is suspected of having) reported as being seropositive for the serological marker of interest.
  • the control or reference value comprises 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 EU.
  • a quartile sum scores are calculated using, for example, the methods reported in Landers C J, Cohavy O, Misra R. et al, Selected loss of tolerance evidenced by Crohn's disease-associated immune responses to auto- and microbial antigens. Gastroenterology (2002)123:689-699.
  • methods comprise quantifying a protein in a biological sample of the subject.
  • methods for protein quantification include immunohistochemistry and immunocytochemistry with detectable markers (e.g., dyes, fluorescence, luminescence).
  • a gold standard for protein quantification is an enzyme-linked immunosorbent assay (ELISA).
  • the ELISA is fixed.
  • the fixed ELISA comprises fixed granulocytes.
  • methods comprise quantifying the protein to obtain a protein quantity and comparing the protein quantity to a reference protein quantity.
  • the reference protein quantity if a protein quantity in a corresponding biological sample from a reference subject.
  • the reference subject may have an IBD.
  • the reference subject may have the same IBD as the subject.
  • the reference subject may have the same IBD that the subject is suspected of having.
  • the reference subject may not have an IBD.
  • the reference subject may not have the same IBD as the subject.
  • the reference subject may not have the same IBD that the subject is suspected of having.
  • the reference subject may be a healthy subject (not diagnosed with any disease or condition).
  • the reference subject may be diagnosed with any inflammatory condition.
  • methods comprise quantifying a marker (e.g., biomarker, serological marker) quantity and a reference marker quantity and detecting a difference between the marker quantity and the reference quantity.
  • methods comprise detecting a marker quantity and detecting multiple reference marker quantities and detecting that the marker quantity falls within a range of reference marker quantities.
  • methods comprise detecting a marker quantity and detecting multiple reference marker quantities and detecting that the marker quantity falls outside a range of reference marker quantities.
  • Methods may comprise detecting a statistically significant difference between a marker quantity and one or more reference quantities. Statistical significance may be determined by a variety of methods.
  • compositions useful for the detection of a genotype or biomarker in a sample obtained from a subject according to the methods described herein are compositions useful for the detection of a genotype or biomarker in a sample obtained from a subject according to the methods described herein. Aspects disclosed herein provide compositions comprises a polynucleotide sequence comprising at least 10 but less than 50 contiguous nucleotides of any one of SEQ ID NOS: 32-124, or reverse complements thereof, wherein the contiguous polynucleotide sequence comprises a detectable molecule.
  • the contiguous nucleotides are suitable to detect a genotype comprising rsl l3435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs6732874A, rs55862430G,
  • compositions comprising an antibody or antigen-binding fragment that specifically binds to GPR35, or a portion thereof, wherein the antibody or antigen-binding fragment comprises a detectable molecule.
  • the antibody comprises a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a Fab, a Fab’, a F(ab’)2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody, a diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, or a bispecific antibody.
  • the antibody or antigen-binding fragment comprises an IgG antibody, an IgM antibody, and/or an IgE antibody.
  • the detectable molecule comprises a fluorophore.
  • the antibody or antigen-binding fragment is conjugated to a paramagnetic particle (e g., bead).
  • kits useful for detecting the genotypes and/or biomarkers disclosed herein may be used to diagnose and/or treat a disease or condition in a sub j ect; or select a patient for treatment and/or monitor a treatment disclosed herein.
  • the kit comprises the compositions described herein, which can be used to perform the methods described herein.
  • Kits comprise an assemblage of materials or components, including at least one of the compositions.
  • the kit contains a composition including of the pharmaceutical composition, for the treatment of IBD.
  • the kits contains all of the components necessary and/or sufficient to perform an assay for detecting and measuring IBD markers, including all controls, directions for performing assays, and any necessary software for analysis and presentation of results.
  • kits described herein comprise components for detecting the presence, absence, and/or quantity of a target nucleic acid and/or protein described herein.
  • the kit further comprises components for detecting the presence, absence, and/or quantity of a serological marker described herein.
  • the kit comprises the compositions (e g., primers, probes, antibodies) described herein.
  • the disclosure provides kits suitable for assays such as enzyme-linked immunosorbent assay (ELISA), single -molecular array (Simoa), PCR, and qPCR.
  • ELISA enzyme-linked immunosorbent assay
  • Simoa single -molecular array
  • PCR qPCR.
  • the exact nature of the components configured in the kit depends on its intended purpose. For example, some embodiments are configured for the purpose of treating a disease or condition disclosed herein (e.g., IBD, CD, UC) in a subject. In some embodiments, the kit is configured particularly for the purpose of treating mammalian subjects.
  • the kit is configured particularly for the purpose of treating human subjects. In further embodiments, the kit is configured for veterinary applications, treating subjects such as, but not limited to, farm animals, domestic animals, and laboratory animals. In some embodiments, the kit is configured to select a subject for a therapeutic agent, such as those disclosed herein. In some embodiments, the kit is configured to select a subject for treatment with an activator of GPR35 activity or expression.
  • kits that comprise a set of oligonucleotides for detecting a combination of single nucleotide polymorphisms selected from rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402, rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598,
  • kits comprising a set of oligonucleotides for detecting a genotype comprising rsl 13435444G, rs3749171A, rs4676406A, rs4676399C, rs2975782A, rs3749172C, rs79844648G, rs4676402A, rs2975780A, rs4676396A, rs6735672A, rs34228697A, rs4676401A, rs2975786G, rs4676346A, rs6437356A, rs6745185C, rs4676407G, rs2953156G, rs4335944C, rs73999973A, rs4676410A, rs4676405G, rs2953154G, rs
  • kits disclosed herein comprise a microarray chip, wherein the microarray comprises oligonucleotide probes on the microarray chip.
  • probes are provided in SEQ ID NOS: 32-124.
  • a probe is at least 90% identical to a probe provided in SEQ ID NOS: 32-124.
  • a probe is at least 95% identical to a probe provided in SEQ ID NOS: 32-124.
  • a probe is at least 97% identical to a probe provided in SEQ ID NOS: 32-124.
  • a probe is at least 98% identical to a probe provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 90% identical to a complement of a probe provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 95% identical to a complement of a probe provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 97% identical to a complement of a probe provided in SEQ ID NOS: 32-124. In some instances, a probe is at least 98% identical to a complement of a probe provided in SEQ ID NOS: 32- 124.
  • kits disclosed herein comprise an oligonucleotide primer that is capable of amplifying a portion of a GPR35 gene locus. In some instances, kits disclosed herein comprise an oligonucleotide primer pair that is capable of amplifying a portion of a GPR35 gene locus. In some instances, kits disclosed herein further comprise a probe that is useful for performing Q-PCR with the oligonucleotide primer(s).
  • An oligonucleotide primer may be complementary to a portion of an exon of the GPR35 gene locus. An oligonucleotide primer may be complementary to a portion of an intron of the GPR35 gene locus.
  • kits disclosed herein comprise a probe for a protein.
  • the probe is an antibody or antigen binding antibody fragment.
  • the probe is an antigen.
  • the probe is a peptide comprising an antigen epitope.
  • the probe comprises a small molecule or peptide that can bind the protein.
  • the probe is labeled with a detectable signal.
  • the probe comprises a detectable signal.
  • the protein is an enzyme and the probe is a substrate. Methods may comprise detecting components of the substrate after it has been processed by the enzyme.
  • the protein may be a serological marker.
  • the serological marker is an anti -Saccharomyces cerevisiae antibody (ASCA). In some instances, the serological marker is an anti -neutrophil cytoplasmic antibody (ANCA). In some instances, the serological marker is an E.coli outer membrane porin protein C (OmpC).
  • the kit may comprise an enzyme-linked immunosorbent assay (ELISA), or immunohistochemistry reagent.
  • ELISA enzyme-linked immunosorbent assay
  • the ELISA may comprise fixed neutrophils as described in Saxon et ak, J Allergy Clin Immunol 1990 86:202-210, incorporated herein by reference.
  • Kits and methods comprise oligonucleotides or uses thereof.
  • the oligonucleotide is a probe.
  • the probe comprises a sequence in SEQ ID NOS: 32- 124, or a complement thereof.
  • the probe comprises a sequence, or a complement thereof, that is at least about 85% identical to a sequence in SEQ ID NOS: 32-124.
  • the probe comprises a sequence, or a complement thereof, that is at least about 90% identical to a sequence in SEQ ID NOS: 32-124.
  • the probe comprises a sequence, or a complement thereof, that is at least about 95% identical to a sequence in SEQ ID NOS: 32-124.
  • the probe comprises a sequence, or a complement thereof, that is identical to at least about 10 nucleotides, at least about 15 nucleotides, at least about 20 nucleotides, at least about 25 nucleotides, at least about 30 nucleotides, at least about 35 nucleotides, at least about 40 nucleotides, or at least about 45 nucleotides of a sequence provided in SEQ ID NOS: 32-124.
  • the oligonucleotide is a primer.
  • the primer is capable of amplifying a region surrounding the polymorphism.
  • the oligonucleotide is capable of binding to a region of a nucleic acid surrounding the polymorphism.
  • the region surrounding the polymorphism is a sequence provided in SEQ ID NOS: 32-124, or a complement thereof.
  • the region surrounding the polymorphism is at least about 80%, at least about 85%, at least about 90%, at least about 95% or at least about 98% identical to a sequence provided in SEQ ID NOS: 32-124, or a complement thereof.
  • the region surrounding the polymorphism comprises at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90 or at least about 100 consecutive nucleotides of a sequence provided in SEQ ID NOS: 32-124, or a complement thereof.
  • kits for use may be included in the kit.
  • the kit also contains other useful components, such as, diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipetting or measuring tools, bandaging materials or other useful paraphernalia.
  • the materials or components assembled in the kit can be provided to the practitioner stored in any convenient and suitable ways that preserve their operability and utility.
  • the components can be in dissolved, dehydrated, or lyophilized form; they can be provided at room, refrigerated or frozen temperatures.
  • the components are typically contained in suitable packaging material (s).
  • suitable packaging material refers to one or more physical structures used to house the contents of the kit, such as compositions and the like.
  • the packaging material is constructed by well-known methods, preferably to provide a sterile, contaminant-free environment.
  • the packaging materials employed in the kit are those customarily utilized in gene expression assays and in the administration of treatments.
  • the term“package” refers to a suitable solid matrix or material such as glass, plastic, paper, foil, and the like, capable of holding the individual kit components.
  • a package can be a glass vial or prefilled syringes used to contain suitable quantities of the pharmaceutical composition.
  • the packaging material has an external label which indicates the contents and/or purpose of the kit and its components.
  • systems for detecting a genotype e.g., one or more SNPs
  • systems for detecting a subject’s response to a therapeutic agent disclosed herein The response may be a change in gene expression in a cell of the subject.
  • systems may be configured to analyze gene expression in a biological sample obtained from a subject.
  • the response may be a change in protein quantity or protein activity.
  • Systems may be configured to quantify an RNA.
  • Systems may be configured to quantify a protein.
  • Systems may be configured to assess a protein’s activity.
  • the protein may be GPR35.
  • the protein may be a protein that interacts with GPR35.
  • the protein may be a protein that functions downstream of GPR35.
  • the protein may be a protein that functions upstream of GPR35.
  • the system is configured to implement the methods described in this disclosure, including, but not limited to, analyzing genes or gene expression products from the genes of a subject to determine whether the subject is, or is susceptible to being, non -responsive to a therapeutic agent disclosed herein.
  • a system for detecting a SNP disclosed herein in a biological sample from a subject comprising: (a) a computer processing device, optionally connected to a computer network; and (b) a software module executed by the computer processing device to analyze a gene or gene expression product from GPR35 in a biological sample from a subject.
  • a system for detecting a subject’s response to a therapeutic agent disclosed herein comprising: (a) a computer processing device, optionally connected to a computer network; and (b) a software module executed by the computer processing device to analyze a gene or gene expression product from GPR35 in a biological sample from a subject.
  • a system for detecting a subject’s response to a therapeutic agent disclosed herein comprising: (a) a computer processing device, optionally connected to a computer network; and (b) a software module executed by the computer processing device to analyze GPR35 activity in a biological sample from a subject.
  • a system for detecting a subject’s response to a therapeutic agent disclosed herein comprising: (a) a computer processing device, optionally connected to a computer network; and (b) a software module executed by the computer processing device to analyze GPR35 interactions with other proteins in a biological sample from a subject.
  • a system for detecting a subject’s response to a therapeutic agent disclosed herein comprising: (a) a computer processing device, optionally connected to a computer network; and (b) a software module executed by the computer processing device to analyze proteins that function downstream of GPR35 in a biological sample from a subject.
  • Proteins that function downstream of GPR35 may include components of intracellular signaling pathways.
  • G protein-coupled receptors often trigger intracellular signaling pathways involving Rho GTPases, phospholipases, ERK proteins, protein kinases, and AKT. Such signaling may also result in intracellular amounts of cAMP, ATP, calcium, etc.
  • systems comprise a central processing unit (CPU), memory (e g., random access memory, flash memory), electronic storage unit, computer program, communication interface to communicate with one or more other systems, and any combination thereof.
  • systems are coupled to a computer network, for example, the Internet, intranet, and/or extranet that is in communication with the Internet, a telecommunication, or data network.
  • systems comprise a storage unit to store data and information regarding any aspect of the methods described in this disclosure.
  • Various aspects of systems are a product or article or manufacture.
  • One feature of a computer program includes a sequence of instructions, executable in the digital processing device’s CPU, written to perform a specified task.
  • ccomputer readable instructions are implemented as program modules, such as functions, features, Application Programming Interfaces (APIs), data structures, and the like, that perform particular tasks or implement particular abstract data types.
  • APIs Application Programming Interfaces
  • a computer program may be written in various versions of various languages.
  • a computer program comprises one sequence of instructions or a plurality of sequences of instructions.
  • a computer program may be provided from one location.
  • a computer program may be provided from a plurality of locations.
  • a computer program includes one or more software modules.
  • a computer program includes, in part or in whole, one or more web applications, one or more mobile applications, one or more standalone applications, one or more web browser plug-ins, extensions, add ins, or add-ons, or combinations thereof.
  • a computer program includes a web application.
  • a web application may utilize one or more software frameworks and one or more database systems.
  • a web application for example, is created upon a software framework such as Microsoft® .NET or Ruby on Rails (RoR).
  • a web application in some instances, utilizes one or more database systems including, by way of non limiting examples, relational, non-relational, feature oriented, associative, and XML database systems. Suitable relational database systems include, by way of non-limiting examples, Microsoft® SQL Server, mySQLTM, and Oracle®.
  • a web application may be written in one or more versions of one or more languages.
  • a web application is written in one or more markup languages, presentation definition languages, client-side scripting languages, server-side coding languages, database query languages, or combinations thereof.
  • a web application is written to some extent in a markup language such as Hypertext Markup Language (HTML), Extensible Hypertext Markup Language (XHTML), or extensible Markup Language (XML).
  • a web application is written to some extent in a presentation definition language such as Cascading Style Sheets (CSS).
  • CSS Cascading Style Sheets
  • a web application is written to some extent in a client-side scripting language such as Asynchronous Javascript and XML (AJAX), flash® Actionscript, Javascript, or Silverlight®.
  • AJAX Asynchronous Javascript and XML
  • a web application is written to some extent in a server-side coding language such as Active Server Pages (ASP), ColdFusion®, Perl, JavaTM, JavaServer Pages (JSP), Hypertext Preprocessor (PHP), PythonTM, Ruby, Tel, Smalltalk, WebDNA®, or Groovy.
  • a web application is written to some extent in a database query language such as Structured Query Language (SQL).
  • SQL Structured Query Language
  • a web application may integrate enterprise server products such as IBM® Lotus Domino®.
  • a web application may include a media player element.
  • a media player element may utilize one or more of many suitable multimedia technologies including, by way of non-limiting examples, Adobe® Flash®, HTML 5, Apple® QuickTime®, Microsoft® Silverlight®, JavaTM, and Unity®
  • a computer program includes a mobile application provided to a mobile digital processing device.
  • the mobile application may be provided to a mobile digital processing device at the time it is manufactured.
  • the mobile application may be provided to a mobile digital processing device via the computer network described herein.
  • a mobile application is created by techniques known to those of skill in the art using hardware, languages, and development environments known to the art. Those of skill in the art will recognize that mobile applications may be written in several languages. Suitable programming languages include, by way of non-limiting examples, C, C++, C#, Featureive-C, JavaTM, Javascript, Pascal, Feature Pascal, PythonTM, Ruby, VB.NET, WML, and XHTML/HTML with or without CSS, or combinations thereof.
  • Suitable mobile application development environments are available from several sources. Commercially available development environments include, by way of non-limiting examples, AirplaySDK, alcheMo, Appcelerator®, Celsius, Bedrock, Flash Lite, .NET Compact Framework, Rhomobile, and WorkLight Mobile Platform. Other development environments may be available without cost including, by way of non-limiting examples, Lazarus, MobiFlex, MoSync, and
  • Phonegap mobile device manufacturers distribute software developer kits including, by way of non-limiting examples, iPhone and iPad (iOS) SDK, AndroidTM SDK, BlackBerry® SDK, BREW SDK, Palm® OS SDK, Symbian SDK, webOS SDK, and Windows® Mobile SDK.
  • iOS iPhone and iPad
  • AndroidTM SDK AndroidTM SDK
  • BlackBerry® SDK BlackBerry® SDK
  • BREW SDK Palm® OS SDK
  • Symbian SDK Symbian SDK
  • webOS SDK webOS SDK
  • Windows® Mobile SDK Windows® Mobile SDK
  • a computer program includes a standalone application, which is a program that may be run as an independent computer process, not an add-on to an existing process, e g ., not a plug-in.
  • a compiler is a computer program(s) that transforms source code written in a programming language into binary feature code such as assembly language or machine code. Suitable compiled programming languages include, by way of non-limiting examples, C, C++, Featureive-C, COBOL, Delphi, Eiffel, JavaTM, Lisp, PythonTM, Visual Basic, and VB .NET, or combinations thereof. Compilation may be often performed, at least in part, to create an executable program.
  • a computer program includes one or more executable complied applications.
  • a computer program in some aspects, includes a web browser plug-in.
  • a plug in in some instances, is one or more software components that add specific functionality to a larger software application.
  • Makers of software applications may support plug-ins to enable third-party developers to create abilities which extend an application, to support easily adding new features, and to reduce the size of an application.
  • plug-ins enable customizing the functionality of a software application.
  • plug-ins are commonly used in web browsers to play video, generate interactivity, scan for viruses, and display particular file types.
  • the toolbar may comprise one or more web browser extensions, add-ins, or add-ons.
  • the toolbar may comprise one or more explorer bars, tool bands, or desk bands.
  • plug-in frameworks are available that enable development of plug-ins in various programming languages, including, by way of non-limiting examples, C++, Delphi, JavaTM, PHP, PythonTM, and VB .NET, or combinations thereof.
  • Web browsers are software applications, designed for use with network-connected digital processing devices, for retrieving, presenting, and traversing information resources on the World Wide Web.
  • Suitable web browsers include, by way of non-limiting examples, Microsoft® Internet Explorer®, Mozilla® Firefox®, Google® Chrome, Apple® Safari®, Opera Software® Opera®, and KDE Konqueror.
  • the web browser in some instances, is a mobile web browser.
  • Mobile web browsers also called
  • mircrobrowsers, mini-browsers, and wireless browsers may be designed for use on mobile digital processing devices including, by way of non-limiting examples, handheld computers, tablet computers, netbook computers, subnotebook computers, smartphones, music players, personal digital assistants (PDAs), and handheld video game systems.
  • mobile web browsers include, by way of non-limiting examples, Google® Android® browser, RIM BlackBerry® Browser, Apple®
  • the medium, method, and system disclosed herein comprise one or more softwares, servers, and database modules, or use of the same.
  • software modules may be created by techniques known to those of skill in the art using machines, software, and languages known to the art.
  • the software modules disclosed herein may be implemented in a multitude of ways.
  • a software module comprises a file, a section of code, a programming feature, a programming structure, or combinations thereof.
  • a software module may comprise a plurality of files, a plurality of sections of code, a plurality of programming features, a plurality of programming structures, or combinations thereof.
  • the one or more software modules comprises a web application, a mobile application, and/or a standalone application.
  • Software modules may be in one computer program or application.
  • Software modules may be in more than one computer program or application.
  • Software modules may be hosted on one machine.
  • Software modules may be hosted on more than one machine.
  • Software modules may be hosted on cloud computing platforms.
  • Software modules may be hosted on one or more machines in one location.
  • Software modules may be hosted on one or more machines in more than one location.
  • the medium, method, and system disclosed herein comprise one or more databases, or use of the same.
  • databases are suitable for storage and retrieval of geologic profile, operator activities, division of interest, and/or contact information of royalty owners.
  • Suitable databases include, by way of non limiting examples, relational databases, non-relational databases, feature oriented databases, feature databases, entity-relationship model databases, associative databases, and XML databases.
  • a database is internet-based.
  • a database is web-based.
  • a database is cloud computing-based.
  • a database may be based on one or more local computer storage devices.
  • the subject matter described herein including methods for obtaining and analyzing a molecular signature from a subject having a pigmented skin lesion, methods for obtaining a pigmented skin lesion, corresponding transmission of data, in certain aspects, are configured to be performed in one or more facilities at one or more locations. Facility locations are not limited by country and include any country or territory. In some instances, one or more steps for obtaining a molecular signature from a sample are performed in a different country than another step of the method. In some instances, one or more steps for obtaining a sample are performed in a different country than one or more steps for obtaining a molecular signature from a sample.
  • one or more method steps involving a computer system are performed in a different country than another step of the methods provided herein.
  • data processing and analyses are performed in a different country or location than one or more steps of the methods described herein.
  • one or more articles, products, or data are transferred from one or more of the facilities to one or more different facilities for analysis or further analysis.
  • An article includes, but is not limited to, one or more components obtained from the genotyping assay, processed cellular material, data, and any article or product disclosed herein as an article or product.
  • Processed cellular material includes, but is not limited to, cDNA reverse transcribed from RNA.
  • RNA includes, but is not limited to, information regarding the gene expression profile of one or more target genes, information regarding a gene sequence profile signature, information regarding a protein sequence profile, information regarding the characteristic of a pigmented skin lesion (e.g., non-melanoma, melanoma in situ, invasive melanoma, stage 1 melanoma, stage 2 melanoma, stage 3 melanoma, stage 4 melanoma), and any data produced by the methods disclosed herein.
  • a pigmented skin lesion e.g., non-melanoma, melanoma in situ, invasive melanoma, stage 1 melanoma, stage 2 melanoma, stage 3 melanoma, stage 4 melanoma
  • Information regarding a pigmented skin lesion includes, but is not limited to, identification of melanoma, likelihood of treatment success for a subject having melanoma, identification of progression of a melanoma, identification of melanoma in situ, identification of invasive melanoma, and identification of a melanoma stage (e.g., 0, 1, 2, 3, 4).
  • any step of any method described herein is performed by a software program or module on a computer.
  • data from any step of any method described herein is transferred to and from facilities located within the same or different countries, including analysis performed in one facility in a particular location and the data shipped to another location or directly to an individual in the same or a different country.
  • data from any step of any method described herein (including characterization of melanoma in situ and/or invasive melanoma, information regarding cellular material such as DNA, RNA, and protein as well as transformed data, e.g.
  • a molecular signature, from cellular material is transferred to and/or received from a facility located within the same or different countries, including analysis of a data input, such as cellular material, performed in one facility in a particular location and corresponding data transmitted to another location, or directly to an individual, such as data related to the diagnosis, prognosis, responsiveness to therapy, or the like, in the same or different location or country.
  • a computer system for evaluating a sample from a subject comprising: a) a central computing environment; b) an input device operatively connected to said central computing environment, wherein said input device is configured to receive a presence or absence of a genotype that correlates with a disease state in the sample; c) a trained algorithm executed by said central computing environment, wherein the trained algorithm is configured to use the presence or absence of the genotype to classify said sample as a disease or normal sample; and d) an output device operatively connected to said central computing environment, wherein said output device is configured to provide information on the classification to a user.
  • the disease state comprises an inflammatory disease or condition.
  • the disease state an inflammatory bowel disease or a subclinical phenotype thereof.
  • the subclinical phenotype comprises stricturing, non-stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g. , ileum, colon, ileocolonic, upper GI, rectum), perianal CD, medically refractory UC, pancolitis, arthralgia, spondylitis (Bechterew’s disease), and any combination thereof.
  • the sample comprises whole blood, plasma, serum, or tissue.
  • the genotype comprises rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs467640l, rs2975786, rs4676346 , rs6437356, rs6745 l85, rs4676407, rs2953 l56, rs4335944 , rs73999973, rs46764l0 , rs4676405, rs2953154, rs6732874, rs55862430, rsl262l598, r
  • genotype comprises at least one of a polymorphism selected from (i) a“G” allele in rsl 13435444, (ii) an“A” allele in rs3749171, (iii) an“A” allele in rs4676406, (iv) a“C” allele in rs4676399 , (v) an “A” allele in rs2975782, (vi) a“C” allele in rs3749172, (vii) a“G” allele in rs79844648 , (viii) an“A” allele in rs4676402, (ix) an“A” allele in rs2975780, (x) an“A” allele in rs4676396, (xi) an“A” allele in rs6735672, (xii) an“A” allele in rs34228697, (xi) a polymorphism selected from (i)
  • the computer system of any previous embodiment wherein said output device provides a report summarizing said information on said classification.
  • said report comprises a recommendation for treatment of said disease state.
  • the computer system of embodiment 10 wherein the treatment comprises administration of modulator of GPR35 activity or expression.
  • the modulator of GPR35 activity or expression comprises an antibody or antigen -binding fragment, peptide, or small molecule.
  • the modulator of GPR35 comprises a compound of Formula I-XXVI.
  • said genotype is determined with an assay comprising polymerase chain reaction (PCR), quantitative reverse-transcription PCR (qPCR), automated sequencing, genotype array, or a combination thereof.
  • PCR polymerase chain reaction
  • qPCR quantitative reverse-transcription PCR
  • compositions comprising one or more binding agents for generating a report that classifies a sample from a subject as disease or non-disease state, wherein the one or more binding agents specifically bind to at least one of SEQ ID NOS: 1-124.
  • generating the report further comprises: (a) providing the sample from the subject; (b) assaying the sample from the subject for detecting the presence of the one or more polymorphisms in one or more genes; (c) generating the report based on the result of step (b); and (d) determining whether said subject has or is likely to have the disease based on the results of step (b).
  • embodiment 15 or 16 wherein the disease state comprises an inflammatory bowel disease or a subclinical phenotype thereof.
  • the disease state comprises inflammatory bowel disease (IBD), Crohn’s disease (CD), ulcerative colitis (UC), or a subclinical phenotype thereof.
  • the subclinical phenotype comprises stricturing, non- stricturing, penetrating, stricturing and penetrating, non-response to anti-TNF alpha treatment, loss of response to TNF alpha treatment, time to first surgery, time to second surgery, disease location (e.g.
  • assaying the sample from the subject for detecting the presence of the one or more polymorphisms of step (b) comprises: (i) contacting the sample with the one or more binding agents that specifically bind to the one or more polymorphisms; and (ii) determining whether the sample specifically binds to said one or more binding agents, wherein binding of the sample to the one or more binding agents indicates the presence of the polymorphism in the subject.
  • assaying the sample from the subject for detecting the presence of the one or more polymorphisms of step (b) comprises sequencing of the sample.
  • step (b) comprises quantifying the amount of DNA comprising the at least one of SEQ ID NOS: 1-124.
  • step (b) comprises quantifying the amount of DNA comprising the at least one of SEQ ID NOS: 1-124.
  • step (b) comprises quantifying the amount of DNA comprising the at least one of SEQ ID NOS: 1-124.
  • step (b) comprises quantifying the amount of DNA comprising the at least one of SEQ ID NOS: 1-124.
  • the quantifying comprises PCR.
  • the use of embodiment 23, wherein the PCR comprises real-time PCR.
  • the quantifying comprises hybridization.
  • a composition comprising one or more binding agents that specifically bind to at least one of (i) rsl l3435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442 , rs74991608, rs348269
  • composition of embodiment 26, wherein the one or more binding agents comprise oligonucleotides.
  • the oligonucleotides comprise RNA or DNA.
  • the one or more binding agents comprise aptamers, antibodies, peptide nucleic acids, or pyranosyl RNA.
  • kits for detecting an inflammatory disease or condition comprising: (a) at least one binding agent that specifically binds to at least one of (i) rsl 13435444, rs3749171, rs4676406, rs4676399, rs2975782, rs3749172, rs79844648, rs4676402,rs2975780, rs4676396, rs6735672 , rs34228697, rs4676401, rs2975786, rs4676346 , rs6437356, rs6745185, rs4676407, rs2953156, rs4335944 , rs73999973, rs4676410 , rs4676405, rs2953154, rs6732874, rs55862430, rsl2621598, rs55919442
  • the kit of embodiment 30, wherein the at least one binding agent comprises at least one oligonucleotide.
  • the at least one binding agent comprises at least one aptamer, antibody, peptide nucleic acid, or pyranosyl RNA.
  • a system for generating a report that classifies a sample a disease or non-disease of a disease state comprising: (a) a computer system that; (i) generates a molecular profile of a DNA sample based upon the presence of at least one polymorphism, or their complement; and (ii) generates a report that classifies the sample based on said molecular profile; and (b) a computer screen that displays said report.
  • the system of embodiment 35 wherein the presence of the at least one polymorphism is based on the result of an assay of said DNA sample, which result is entered into a database.
  • the system of embodiment 35 or 36 further comprising an input for said result.
  • Systems and kits disclosed herein may comprise a protein, polypeptide, nucleic acid, or fragment thereof that is detectably labeled.
  • methods disclosed herein may comprise labeling a protein, polypeptide, nucleic acid, or fragment thereof, or use of a protein, polypeptide, nucleic acid, or fragment thereof that is detectably labeled.
  • the protein, polypeptide, nucleic acid, or fragment thereof is ligated to an adaptor and the adapter is detectably labeled.
  • the detectable label may comprise a fluorescent label, e.g., by incorporation of nucleotide analogues.
  • labels suitable for use in the present invention include, but are not limited to, biotin, iminobiotin, antigens, cofactors, dinitrophenol, lipoic acid, olefmic compounds, detectable polypeptides, electron rich molecules, enzymes capable of generating a detectable signal by action upon a substrate, and radioactive isotopes.
  • the detectable label is a radioactive isotope.
  • Radioactive isotopes by way of non-limiting example, include 32 P and 14 C.
  • Fluorescent molecules suitable for the present invention include, but are not limited to, fluorescein and its derivatives, rhodamine and its derivatives, texas red, 5’carboxy-fluorescein (“FAM”), 2’, 7’-dimethoxy-4’, 5’-dichloro-6-carboxy-fluorescein (“JOE”), N, N, N’, N’-tetramethyl-6-carboxy-rhodamine ( TAMRA ). 6-carboxy-X-rhodamine (“ROX”), HEX, TET, IRD40, and IRD41.
  • Fluorescent molecules which are suitable for use with systems, kits and methods disclosed herein include: cyamine dyes, including but not limited to Cy2, Cy3, Cy3.5, CY5, Cy5.5, Cy7 and FLUORX; BODIPY dyes including but not limited to BODIPY-FL, BODIPY-TR, BODIPY-TMR, BODIPY-630/650, and BODIPY -650/670; and ALEXA dyes, including but not limited to ALEXA - 488, ALEXA -532, ALEXA-546, ALEXA -568, and ALEXA-594; as well as other fluorescent dyes which will be known to those who are skilled in the art.
  • Electron rich indicator molecules suitable for the present invention include, but are not limited to, ferritin, hemocyanin and colloidal gold.
  • Two-color fluorescence labeling and detection schemes may also be used (Shena et ak, 1995, Science 270:467-470). Use of two or more labels can be useful in detecting variations due to minor differences in experimental conditions (e.g. , hybridization conditions). In some embodiments of the invention, at least 5, 10, 20, or 100 dyes of different colors can be used for labeling. Such labeling would also permit analysis of multiple samples simultaneously which is encompassed by the invention.
  • Labeled molecules may be are contacted to a plurality of oligonucleotide probes under conditions that allow sample nucleic acids having sequences complementary to the probes to hybridize thereto (e.g., an array or chip).
  • the hybridization signal may be detected using methods well known to those of skill in the art including, but not limited to, X-Ray film, phosphor imager, or CCD camera.
  • fluorescently labeled probes the fluorescence emissions at each site of a transcript array may be detected by scanning confocal laser microscopy. In one embodiment, a separate scan, using the appropriate excitation line, is carried out for each of the two fluorophores used.
  • a laser is used that allows simultaneous specimen illumination at wavelengths specific to the two fluorophores and emissions from the two fluorophores may be analyzed simultaneously (see Shalon et al. (1996) Genome Res. 6, 639-645).
  • the arrays are scanned with a laser fluorescence scanner with a computer controlled X-Y stage and a microscope objective. Sequential excitation of the two fluorophores is achieved with a multi-line, mixed gas laser, and the emitted light is split by wavelength and detected with two photomultiplier tubes.
  • fluorescence laser scanning devices are described, e.g. , in Schena et al. (1996) Genome Res. 6, 639-645.
  • a fiber-optic bundle can be used such as that described by Ferguson et al. (1996) Nat. Biotech. 14, 1681-1684.
  • the resulting signals can then be analyzed to determine the expression of GPR35 and housekeeping genes, using computer software.
  • the amplification can comprise cloning regions of genomic DNA of the subject.
  • amplification of the DNA regions is achieved through the cloning process.
  • expression vectors can be engineered to express large quantities of particular fragments of genomic DNA of the subject (Sambrook and Russel, Molecular Cloning: A Laboratory Manual 4 th ed , Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2012)).
  • the amplification comprises expressing a nucleic acid encoding a gene, or a gene and flanking genomic regions of nucleic acids, from the subject.
  • RNA pre-messenger RNA
  • RNA pre-messenger RNA
  • the genomic DNA, or pre-RNA, of a subject may be fragmented using restriction endonucleases or other methods. The resulting fragments may be hybridized to SNP probes.
  • a DNA sample of a subject for use in hybridization may be about 400 ng, 500 ng, 600 ng, 700 ng, 800 ng, 900 ng, or 1000 ng of DNA or greater.
  • methods are used that require very small amounts of nucleic acids for analysis, such as less than 400 ng, 300 ng, 200 ng, 100 ng, 90 ng, 85 ng, 80 ng, 75 ng, 70 ng, 65 ng, 60 ng, 55 ng, 50 ng, or less, such as is used for molecular inversion probe (MIP) assays.
  • MIP molecular inversion probe
  • Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion ⁇ 0.75) were included in the analysis. Time to first and second surgery was calculated using Cox Proportional Hazards Regression analysis (PLINK). Table 2 shows SNPs that were significantly correlated with a time to first surgery in subjects with CD.
  • the allele conferring risk within rsl 13435444 comprises a G.
  • the allele conferring risk within rs4676406 comprises an A.
  • the allele conferring risk within rs4676399 comprises a C
  • the allele conferring risk within rs2975782 comprises an A.
  • the allele conferring risk within rs3749172 comprises a C.
  • the allele conferring risk within rs79844648 comprises a G.
  • the allele conferring risk within rs6437356 comprises an A.
  • the allele conferring risk within rs4676346 comprises an A.
  • the allele conferring risk within rs4676401 comprises an A.
  • the allele conferring risk within rs2975786 comprises a G.
  • the allele conferring risk within rs6745185 comprises a C a.
  • the allele conferring risk within rs4676407 comprises a G.
  • the allele conferring risk within rs2953156 comprises a G.
  • the allele conferring risk within rs4335944 comprises a C.
  • the allele conferring risk within rs4676396 comprises an A at.
  • the allele conferring risk within rs6735672 comprises an A.
  • the allele conferring risk within rs4676402 comprises a.
  • the allele conferring risk within rs2975780 comprises an Althea allele conferring risk within rs4676405 comprises a G.
  • the allele conferring risk within rs2953154 comprises a G.
  • the allele conferring risk within rs6732874 comprises an A.
  • the allele conferring risk within rs55862430 comprises a G.
  • the allele conferring risk within rsl2621598 comprises an A at.
  • the allele conferring risk within rs55919442 comprises an A.
  • Table 3 shows SNPs that were significantly correlated with a second surgery in subjects with CD.
  • the allele conferring risk within rsl 13435444 comprises a G.
  • the allele conferring risk within rs79844648 comprises a G.
  • the allele conferring risk within rs34228697 comprises an A.
  • the allele conferring risk within rs74991608 comprises an A.
  • the allele conferring risk within rs74991608 comprises an G.
  • Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p ⁇ 10 4 ;
  • UC ulcerative colitis
  • Table 8 shows SNPs that were significantly correlated with UC.
  • Table 9 shows data from the Cedars-Sinai cohort replicated in the large International IBD Genetic Consortium (IIBDGC) cohort (n> 200,000,000). Results show that rs3749171A, rs73999973A, rs4676406A, rs2975786G, rs4676410A, rs6437364A, rs4676407G, rs6745185C, rs2953156G, rs6437356A, and rs4335944C, are strongly associated with ulcerative colitis.
  • Genotyping data was produced from resected small bowel tissue samples from patients diagnosed with IBD and healthy patients without IBD. eQTL mapping was performed on these samples. Transcriptomic data was generated on small bowel tissue. Briefly, uninflamed tissue from formalin-fixed paraffin-embedded (FFPE) small bowel resection margins of 100 subjects requiring surgery at Cedars-Sinai Medical Center for Crohn’s disease was identified. Whole-thickness ileal tissue was scraped from the FFPE tissue sections followed by RNA extraction using the RNeasy FFPE kit (Qiagen) according to the manufacturer's instructions.
  • FFPE formalin-fixed paraffin-embedded
  • the Transplex Whole Transcriptome Amplification kit (WTA2; Sigma) was used for cDNA synthesis and amplification. Subsequent purification of the cDNA product was performed with the PCR Purification kit (Qiagen). Sample quality was confirmed using the Agilent Bioanalyzer. For samples passing quality control, Cy5 labeling with the ULST Fluorescent Labeling kit (Kreatech) and hybridization (performed in duplicate for each sample) to Whole Human Genome 4x44k Microarrays (Agilent) was performed. [00292] Single channel microarray expression data extracted using Agilent feature extraction software was received from Genome Technology Access Center at Washington University in St. Louis. Raw expression data available in technical duplicates was normalized using LIMMA package implemented in R version 3.2.2.
  • the expression data preprocessing included background correction of the expression data, followed by log2 -transformation and quantile-normalization Unsupervised hierarchical clustering of expression data was used to remove outlier subjects.
  • cis-eQTL mapping For cis-eQTL mapping, a 1Mb cis distance from gene bounds was used. Cis-eQTLs were defined as association signals from SNPs located within 1 Mb from each of the gene bounds. False discovery rates (FDR) were estimated to correct for multiple testing using Matrix eQTL according to the Benjamini and Hochberg method. Note that FDR calculation in matrix eQTL does not take into account“linkage disequilibrium” between the SNPs and may be overly stringent. A negative beta value indicates a decrease in GPR35 gene expression. A positive beta value indicates an increase in GPR35 gene expression.
  • Genotyping data was produced from resected rectum tissue samples from patients diagnosed with UC and healthy patients without UC. eQTL mapping was performed on these samples. SNP rs34228697 was associated with decreased expression of GPR35. Transcriptomic data was generated on rectum tissue. Briefly, uninflamed tissue from formalin-fixed paraffin-embedded (FFPE) rectum resection margins of 100 subjects requiring surgery at Cedars-Sinai Medical Center for Crohn’s disease was identified. Whole-thickness rectal tissue was scraped from the FFPE tissue sections followed by RNA extraction using the RNeasy FFPE kit (Qiagen) according to the manufacturer's instructions.
  • FFPE formalin-fixed paraffin-embedded
  • the Transplex Whole Transcriptome Amplification kit (WTA2; Sigma) was used for cDNA synthesis and amplification. Subsequent purification of the cDNA product was performed with the PCR Purification kit (Qiagen). Sample quality was confirmed using the Agilent Bioanalyzer. For samples passing quality control, Cy5 labeling with the ULST Fluorescent Labeling kit (Kreatech) and hybridization (performed in duplicate for each sample) to Whole Human Genome 4x44k Microarrays (Agilent) was performed.
  • Genotyping data was collected from a Cedars-Sinai cohort of patients with ulcerative colitis (UC) and patients without UC. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p ⁇ 10 4 ; missingness in SNPs of >2%; minor allele frequency ⁇ 1%. Related individuals (Pi-hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion ⁇ 0.75) were included in the analysis.
  • results showed that the presence of anti-OmpC and ASCA correlated with SNPs in the GPR35 locus as shown in Table 10.
  • a negative beta value indicates a decrease in expression of the serological marker.
  • a positive beta values indicates an increase in expression of the serological marker.
  • the presence of anti-OmpC or ASCA, in addition to at least one of the SNPs of Table 10 is predictive of a risk of a subject developing UC.
  • the allele conferring risk within rs3749171 comprises an A.
  • the allele conferring risk within rs4676399 comprises a C.
  • the allele conferring risk within rs2975782 comprises an A.
  • the allele conferring risk within rs3749172 comprises a C.
  • the allele conferring risk within rs4676402 comprises an A.
  • the allele conferring risk within rs4676346 comprises an A.
  • Genotyping data was collected from a Cedars-Sinai cohort of patients with Crohn’s Disease (CD) and patients without CD. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p ⁇ 10 4 ; missingness in SNPs of >2%; minor allele frequency ⁇ 1%. Related individuals (Pi-hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion ⁇ 0.75) were included in the analysis.
  • the risk allele within rs4676406 comprises an A.
  • the risk allele within rs2975780 comprises an A.
  • the risk allele within rs4676346 comprises an A.
  • Genotyping data was collected from patients diagnosed with ulcerative colitis (UC) with pancolitis or left-sided colitis and UC patients without pancolitis or left-sided colitis. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p ⁇ 10 4 ; missingness in SNPs of >2%; minor allele frequency ⁇ 1%. Related individuals (Pi -hat scores >0.25) were identified using identity -by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals.
  • the allele conferring risk within rs4676402 comprises an A.
  • the allele conferring risk within rs6735672 comprises an A.
  • the allele conferring risk within rs4676399 comprises a C.
  • the allele conferring risk within rs4676396 comprises an A. Table 12.
  • Anti- TNF non-response is characterized by either primary non-response or secondary non-response.
  • Primary non-response refers to a subject not responding to the induction of an anti-TNF therapy.
  • Secondary non-response, or loss of response refers to the loss of response during maintenance after a successful induction of the anti-TNF therapy.
  • Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy- Weinberg Equilibrium p ⁇ 10 4 ; missingness in SNPs of >2%; minor allele frequency ⁇ 1%. Related individuals (Pi -hat scores >0.25) were identified using identity-by-descent and excluded from analysis (PLINK). Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion ⁇ 0.75) were included in the analysis.
  • Admixture was used to generate ethnicity proportion estimations for all individuals. Only subjects identified by admixture as Caucasian (proportion ⁇ 0.75) were included in the analysis. Results showed that SNPs at the GPR35 locus provided in Tables 19-22 are significantly associated with isolated disease in the ileum, colon ileocolonic region of the intestine, and upper GI tract, respectively.
  • Genotyping data was collected from patients with Crohn’s Disease (CD) with morphological defects of ileal Paneth cells, as determined using the classification set forth in VanDussen et al., “Genetic Variants Synthesize the Produce Paneth Cell Phenotypes That Define Subtypes of Crohn’s Disease,” Gastroenterology 2014; 146:200-209. Genotyping was performed at Cedars-Sinai Medical Center using the Illumina Immuno-BeadChip array. Markers were excluded from analysis based on: Hardy-Weinberg Equilibrium p ⁇ 10 4 ; missingness in SNPs of >2%; minor allele frequency ⁇ 1%.

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Abstract

L'invention concerne des procédés, des kits et des compositions pour traiter un sujet atteint d'une maladie abdominale inflammatoire. Ces procédés, kits et compositions peuvent être particulièrement utiles pour des sujets présentant des polymorphismes mononucléotidiques dans un locus de gène codant le récepteur couplé à la protéine G 35 (GPR35).
PCT/US2019/029398 2018-04-27 2019-04-26 Compositions et procédés de ciblage de gpr35 pour le traitement d'une affection abdominale inflammatoire WO2019210203A1 (fr)

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US11773101B2 (en) 2019-01-24 2023-10-03 Prometheus Biosciences, Inc. GPR35 modulators
CN114129562A (zh) * 2020-09-03 2022-03-04 中国科学院大连化学物理研究所 香豆素类衍生物在制备治疗炎症性肠炎药物中应用及药物

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