WO1998054359A1 - Prediction of inflammatory disease associated with il-1 geneloci polymorphisms - Google Patents

Prediction of inflammatory disease associated with il-1 geneloci polymorphisms Download PDF

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WO1998054359A1
WO1998054359A1 PCT/GB1998/001481 GB9801481W WO9854359A1 WO 1998054359 A1 WO1998054359 A1 WO 1998054359A1 GB 9801481 W GB9801481 W GB 9801481W WO 9854359 A1 WO9854359 A1 WO 9854359A1
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seq
marker
allele
alleles
ilirn
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Gordon Duff
Angela Cox
Nicola Jane Camp
Francesco Saverio De Giovine
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Priority to CA002291731A priority Critical patent/CA2291731A1/en
Priority to DE69841588T priority patent/DE69841588D1/de
Priority to AT98922938T priority patent/ATE462800T1/de
Priority to IL13312898A priority patent/IL133128A0/xx
Priority to JP50035899A priority patent/JP2002500513A/ja
Priority to AU75398/98A priority patent/AU755107B2/en
Priority to BR9809183-2A priority patent/BR9809183A/pt
Priority to EA199901097A priority patent/EA199901097A1/ru
Application filed by Individual filed Critical Individual
Priority to EP98922938A priority patent/EP0983385B1/en
Publication of WO1998054359A1 publication Critical patent/WO1998054359A1/en
Priority to US09/345,217 priority patent/US6268142B1/en
Priority to NO995803A priority patent/NO995803L/no
Anticipated expiration legal-status Critical
Priority to US09/845,129 priority patent/US6706478B2/en
Priority to US10/802,061 priority patent/US20040152124A1/en
Priority to US11/121,634 priority patent/US20050282198A1/en
Priority to US11/866,073 priority patent/US20080187920A1/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • C—CHEMISTRY; METALLURGY
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    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
    • 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
    • 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
    • C12Q2600/172—Haplotypes
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
    • Y10T436/143333—Saccharide [e.g., DNA, etc.]

Definitions

  • This invention relates to methods and kits for the identification of susceptibility to immunoinflammatory disorders or disorders modulated by IL-1 biologic activity.
  • the method involves the detection of at least one allele in an IL-1 haplotype, such as the IL-1 (44112332) haplotype or the IL-1 (33221461) haplotype, which is associated with inflammatory disorders, such as coronary artery disease, osteoporosis, nephropathy in diabetes mellitus, alopecia areata, Graves disease, systemic lupus erythamatosus, lichen sclerosis, ulcerative colitis, diabetic retinopathy, periodontal disease, juvenile chronic arthritis, particularly chronic iridocyclitis, psoriasis, insulin dependent diabetes in DR3/4 patients, asthma, chronic inflammatory liver diseases, chronic inflammatory lung disease, lung fibrosis, liver fibrosis, as well as acute and chronic inflammatory diseases of the central nervous system, the cardiovascular system, the gastrointestinal system, the musculoskeletal system
  • Genetic testing also called genetic screening, genotyping or molecular diagnostics
  • Genetic testing can be defined broadly as the testing of nucleic acid of a patient in an analytical capacity to determine if a patient contains mutations (or alleles or polymorphisms) that either cause or increase susceptibility to a disease state or are in "linkage disequilibrium" with the gene causing a disease state.
  • Linkage disequilibrium refers to the tendency of specific alleles to occur together more frequently than would be expected by chance. Alleles at given loci are in equilibrium if the frequency of any particular set of alleles (or haplotype) is the product of their individual population frequencies. The cause of disequilibrium is often unclear. It can be due to selection for certain allele combinations, or to recent admixture of genetically heterogeneous populations. In addition, in the case of markers that are very tightly linked to a disease gene, an association of an allele (or group of linked alleles) with the disease gene is expected if the disease mutation occurred in the recent past, so that sufficient time has not elapsed for equilibrium to be achieved through recombination events in that small chromosomal region.
  • the IL-1 gene cluster is located on the long arm of human chromosome 2 (2ql3) and contains at least the genes for IL-l ⁇ (ILIA), IL-l ⁇ (IL1B), and the IL-1 receptor antagonist (IL1RN) within a region of 430 Kb (Nicklin, et al., Genomics 19: 382-4 (1994)).
  • the agonist molecules, IL-l ⁇ and IL-l ⁇ have potent pro-inflammatory activity and are at the head of many inflammatory cascades.
  • IL-6 and IL-8 Their actions, often via the induction of other cytokines such as IL-6 and IL-8, lead to activation and recruitment of leukocytes into damaged tissue, local production of vasoactive agents, fever response in the brain and the hepatic acute phase response. All three IL-1 molecules bind to type I and to type II IL-1 receptors, but only the type I receptor transduces a signal to the interior of the cell. In contrast, the type II receptor is shed from the cell membrane and acts as a decoy receptor. The receptor antagonist and the type II receptor, therefore, are both anti- inflammatory in their actions.
  • IL-1 Inappropriate production of IL-1 appears to play a central role in the pathology of many autoimmune and inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disorder, psoriasis, and others. In addition, there are stable inter-individual differences in the rates of production of IL-1, and some of this variation may be accounted for by genetic differences at IL-1 gene loci (Molvig, et al., Scand. J. Immunol. 27:705-16 (1988); Pociot, et al., Eur. J. Clin. Invest.
  • IL-1 genes are reasonable candidates for determining part of the genetic susceptibility to inflammatory diseases, most of which have a multifactorial etiology with a polygenic component.
  • Certain alleles from the E -l gene cluster are known to be associated with particular disease states. For example, we have shown that IL1RN allele 2 is associated with coronary artery disease, osteoporosis (U.S. Application Nos. 08/813,416, 08/628,282), nephropathy in diabetes mellitus (Blakemore, et al, Hum. Genet. 97(3): 369-74 (1996)), alopecia areata (Cork, et al, J. Invest. Dermatol. 104(5 Supp.): 15S-16S (1995)), Graves disease (Blakemore, et al, J. Clin.
  • IL1RN cluster allele 1 is associated with diabetic retinopathy (GB Application No. 9618960.0).
  • ILIA allele 2 from marker -889 and ILlB(Taq ⁇ ) allele 2 from marker +3953 are associated with periodontal disease (U.S. S/N 08/510,696).
  • the ILIA allele 2 from marker -889 is also associated with juvenile chronic arthritis, particularly chronic iridocyclitis (McDowell, et al, Arthritis Rheum. 38: 221-28 (1995)).
  • the ILlB(Taq ⁇ ) allele 2 from marker +3953 of IL1B is also associated with psoriasis and insulin dependent diabetes in DR3/4 patients (di Giovine, et al, Cytokine 7: 606 (1995); Pociot, et al, EurJ. Clin. Invest. 22: 396-402 (1992)).
  • the present invention provides a novel method for the early prediction of a propensity to develop inflammatory disorders. It also provides kits for the early determination of said propensity and methods for identifying additional alleles that are associated with these diseases or linked (in linkage disequilibrium) with the haplotype.
  • the method of predicting increased risk for diseases modulated by IL-1 biologic activity consists of detecting the presence of one or more alleles of an IL-1 haplotype, or alternatively, the entire haplotype may be detected.
  • the IL-1 haplotype may be the IL-1 (44112332) haplotype, the IL-1 (33441461) haplotype, or any other haplotype from this region.
  • the haplotype is the IL-1 (44112332) haplotype. Having one or more of the alleles in an IL-1 haplotype indicates increased risk for a variety of inflammatory disorders.
  • IL-1 loci genetic component examples include, but are not limited to, coronary artery disease, osteoporosis, nephropathy in diabetes mellitus, alopecia areata, Graves disease, systemic lupus erythamatosus, lichen sclerosis, ulcerative colitis, periodontal disease, juvenile chronic arthritis particularly chronic iridocyclitis, psoriasis, insulin dependent diabetes in DR3/4 patients, diabetic retinopathy and other diseases with an IL-1 loci genetic component.
  • the IL-1 (44112332) haplotype is associated with the following diseases: coronary artery disease, osteoporosis, nephropathy in diabetes mellitus, alopecia areata, Graves disease, systemic lupus erythamatosus, lichen sclerosis, and ulcerative colitis.
  • the IL-1 (33221461) haplotype is associated with the following diseases: periodontal disease, juvenile chronic arthritis, psoriasis, insulin dependent diabetes, and diabetic retinopathy.
  • the invention can be described as the following: isolating nucleic acid from the patient, identifying one or more alleles present in the IL-1 gene cluster, and comparing the one or more alleles to a control sample.
  • the control sample contains at least one allele from an IL-1 haplotype.
  • a control sample contains one or more of the following alleles from the IL-1 (44112332) haplotype: allele 4 of the 222/223 marker (*132 mu PCR product), allele 4 of the gz5/gz6 marker (*91 mu PCR product), allele 1 of the -889 marker (contains an Ncol site), allele 1 of the +3953 marker (contains two TaqI sites), allele 2 of the -511 marker (contains a Bsu36I site), allele 3 of the gaat.p33330 marker (*197 mu PCR product), allele 3 of the Y31 marker (*160 mu PCR product), allele 2 of the VNTR marker (240 bp PCR product).
  • microsatellite marker PCR products is given in mobility units which approximate the size in base pairs, but may vary according to the method of determination, as would be readily ascertained by one of skill in the art.
  • the markers positions are as indicated by in the references of
  • control sample may also contain the following alleles which may be part of the
  • IL-1 (44112332) haplotype: allele 2 of the 1731 marker of the IL1RN gene (A at position 1731), allele ⁇ of the 1812 marker of the IL1RN gene (A at position 1812), allele 2 of the 1868 marker of the IL1RN gene (G at position 1868), allele 2 of the 1887 marker of the IL1RN gene (C at position 1887), allele 2 of the 8006 marker of the IL1RN gene (contains an Hpall or Mspl site), allele 2 of the 8061 marker of the IL 1RN gene (lacks an Mwol site), allele 2 of the 9589 marker of the IL1RN gene (contains an Sspl site).
  • the markers positions are as indicated by Clay, et al. or Gausch, et al.
  • the control sample may also contain the following alleles from the IL-1 (33221461) haplotype: allele 3 of the 222/223 marker (* 130 mu PCR product), allele 3 of the gz5/gz6 marker (*88 mu PCR product), allele 2 of the -889 marker (lacks an Ncol site), allele 2 of the +3953 marker (contains a TaqI site), allele 1 of the -511 marker (lacks a Bsu36I site), allele 4 of the gaat.p33330 marker (*201 mu PCR product), allele 6 of the Y31 marker (* 166 mu PCR product), allele 1 of the VNTR marker (412 bp PCR product).
  • control sample may also be an allelic ladder comprised of a plurality of the above listed alleles and may also contain additional alleles from the above markers. There may be a plurality of control samples, each containing different alleles or sets of alleles.
  • kits for the detection of alleles that are predictive of inflammatory disease generally includes at least one oligonucleotide complementary to a DNA sequence in the IL-1 gene family and a control sample.
  • the control sample contains an allele known to be associated with inflammatory disease, as described above.
  • the control sample may contain the actual PCR products produced by amplification of said alleles, or alternatively may contain genomic or cloned DNA from an individual that carries an IL-1 haplotype.
  • the kit may also include a DNA sampling means, a DNA purification means, and
  • oligonucleotide may contain a detectable label.
  • the following oligonucleotides, among others, may be present in the kit or used with the methods:
  • ATGTAT AGAATTCC ATTCCTG SEQ ID NO. 1
  • GTGTCCTCAAGTGGATCTGG SEQ ID NO. 12
  • GGGCAACAGAGCAATGTTTCT SEQ ID NO. 13
  • Another embodiment of the invention provides a method of identifying inflammatory endothelial fibroblasts
  • IL-1 haplotype disorders associated with one or more alleles of an IL-1 haplotype, for example the IL-1 (44112332)
  • the method consists of gathering a first group of patients without a particular inflammatory disease, gathering a second group of patients with the inflammatory disease and
  • genotyping the first and second groups at the IL-1 gene cluster If an allele of the IL-1 haplotype is over represented in the second group as compared with the first group, it is identified as associated
  • Another embodiment of the invention provides a method of identifying additional alleles in linkage disequilibrium with an IL-1 haplotype, for example the IL-1 (44112332) haplotype. Additional alleles from the IL-1 gene cluster can be identified by sequence or restriction enzyme analysis of this region of the DNA. Linkage disequilibrium is then established by typing two loci and comparing the observed and expected haplotype frequencies, where the expected frequencies under the null hypothesis of no association are the products of the individual allele frequencies. This comparison can be done using the E.H. program of Xie and Ott (Handbook of Human Genetic Linkage, 1994, John Hopkins University Press, 188-98).
  • Yet another embodiment of the invention is an allelic ladder comprising alleles from the markers described herein.
  • Other embodiments and advantages of the invention are set forth in part in the description which follows, and will be obvious from this description, or may be learned from the practice of the invention.
  • Figure 1 depicts the 8 markers in the IL-1 gene cluster and their approximate location.
  • Figure 2 depicts the correlation between linkage disequilibrium and physical distance.
  • the present invention is directed to methods for the detection of at least one allele of an IL-1 haplotype, including the IL-1 (44112332) haplotype or the IL-1 (33221461) haplotype, that is associated with inflammatory disorders.
  • 'marker refers to a specific site in the genome which exhibits sequence variations between individuals. For example, herein are described at least 8 markers: the 222/223, gz5/gz6, -889, +3953, -511, gaat.p33330, Y31 and VNTR markers.
  • 'allele' refers to the different sequence variants found at given markers.
  • sequence variants may be single or multiple base changes, including insertions, deletions or substitutions or may be variable number of sequence repeats and the like.
  • 'linkage disequilibrium refers to the co-inheritance of two alleles at frequencies greater than would be expected from the separate frequencies of occurrence of each allele in a given control population.
  • the expected frequency of occurrence of two alleles that are inherited independently is the frequency of the first allele multiplied by the frequency of the second allele. Alleles that co-occur at expected frequencies are said to be in 'linkage equilibrium.'
  • haplotype' is a set of alleles that are inherited together as a group (are in linkage disequilibrium). As used herein, haplotype is defined to include those haplotypes that occur at statistically significant levels (p C0IT ⁇ 0.05).
  • IL-1 haplotype' refers to any haplotype in the IL-1 loci.
  • the phrase 'IL-1 (44112332) haplotype' refers to the haplotype consisting of at least: allele 4 of the 222/223 marker of ILIA; allele 4 of the gz5/gz6 marker of ILIA; allele 1 of the -889 marker of ILIA; allele 1 of the +3953 marker of IL1B; allele 2 of the -511 marker of IL1B; allele 3 of the gaat.p33330 marker; allele 3 of the Y31 marker; and allele 2 of the VNTR marker of IL1RN.
  • the phrase 'IL-1 (44112332) haplotype' also includes any additional alleles that are in linkage disequilibrium with this set of alleles.
  • the IL-1 (44112332) haplotype may also contain the following alleles: allele 2 of the 1731 marker of the IL1RN gene (A at position 1731), allele 2 of the 1812 marker of the IL1RN gene (A at position 1812), allele ⁇ of the 1868 marker of the IL1RN gene (G at position 1868), allele 2 of the 1887 marker of the IL1RN gene (C at position 1887), allele 2 of the 8006 marker of the IL1RN gene (contains an Hpall or Mspl site), allele 2 of the 8061 marker of the IL1RN gene (lacks an Mwol site), and allele 2 of the 9589 marker of the IL1RN gene (contains an Sspl site).
  • TL-1 (33221461) haplotype' refers to the haplotype consisting of at least: allele 3 of the 222/223 marker of ILIA; allele 3 of the gz5/gz6 marker of ILIA; allele 2 of the -889 marker of ILIA; allele 2 of the +3953 marker of IL1B; allele 1 of the -511 marker of IL1B; allele 4 of the gaat.p33330 marker; allele 6 of the Y31 marker; and allele 1 of the VNTR marker of IL1RN.
  • the phrase 'IL-1 (33221461) haplotype' also includes any additional alleles that are in linkage disequilibrium with this set of alleles.
  • the phrase 'inflammatory disease' or 'inflammatory disorder/as used herein, refers to those diseases associated with inheritance of an IL-1 haplotype. In addition to conventional diseases of inflammation, the term encompasses those diseases which are not traditionally thought of as inflammatory conditions, but which have an inflammatory component or are modulated by the IL-1 gene cluster, including certain infectious diseases, certain metabolic disorders, and certain aspects of tumor growth, spread and control.
  • Inflammatory disorders include, but are not limited to, coronary artery disease, osteoporosis, nephropathy in diabetes mellitus, alopecia areata, Graves disease, systemic lupus erythamatosus, lichen sclerosis, ulcerative colitis, diabetic retinopathy, periodontal disease, juvenile chronic arthritis particularly chronic iridocychtis, psoriasis, insulin dependent diabetes in DR3/4 patients and other diseases with an IL-1 loci genetic component.
  • the process of 'detecting alleles' is variously described as
  • the allele actually detected might be a disease-causing mutation, or a mutation that is in linkage disequilibrium with a disease-causing mutation. It will be manifest in the genomic DNA of a patient, but may also be detectable from RNA or protein sequences transcribed or translated from this region.
  • 'IL-1 gene cluster' or 'IL-1 loci' or 'IL-1 gene family includes all the nucleic acid at or near 2q 13 on chromosome 2, including the IL 1 A, IL 1 B and IL 1 RN genes and any other linked sequences.
  • 'microsatellite marker what is meant is a marker whose alleles comprise different numbers of short repeat ( ⁇ 5 bp) sequences.
  • VNTR marker By 'VNTR marker' what is meant is a marker whose alleles comprise different numbers of medium length repeat sequences. A specific VNTR marker from intron 2 of the ILIRN gene is described herein.
  • the cytokines in the IL-1 gene cluster play a central role in the immune and inflammatory responses as well as a number of inflammatory diseases.
  • the degree of linkage disequilibrium of the IL-1 gene cluster was investigated and found to be statistically significant at
  • the invention is directed to a method of predicting the propensity or predisposition of a patient to inflammatory disease by genotyping the patient's DNA at the IL-1 gene cluster.
  • the patient's genotype is compared with a control sample that contains one or more alleles from an IL-1 haplotype, such as the IL-1 (44112332) haplotype or the IL-1 (33221461) haplotype.
  • the alleles include: allele 4 of the 222/223 marker (*132 mu PCR product), allele 4 of the gz5/gz6 marker (*91 mu PCR product), allele 1 of the -889 marker (contains an Ncol site), allele 1 of the +3953 marker (contains two TaqI sites), allele 2 of the -511 marker (contains a Bsu36I site), allele 3 of the gaat.p33330 marker (*197 mu PCR product), allele 3 of the Y31 marker (* 160 mu PCR product), allele 2 of the VNTR marker (240 bp PCR product).
  • microsatellite marker PCR products is given in mobility units which approximate the size in base pairs, but may vary according to the method of determination, as would be readily ascertained by one of skill in the art.
  • the control sample may also contain the following alleles which may be part of the IL-1 (44112332) haplotype: allele 2 of the 1731 marker of the ILIRN gene (A at position 1731), allele 2 of the 1812 marker of the ILIRN gene (A at position 1812), allele 2 of the 1868 marker of the ILIRN gene (G at position 1868), allele 2 of the 1887 marker of the ILIRN gene (C at position 1887), allele 2 of the 8006 marker of the ILIRN gene (contains an Hpall or Mspl site), allele 2 of the 8061 marker of the ILIRN gene (lacks an Mwol site), allele 2 of the 9589 marker of the ILIRN gene (contains an Sspl site).
  • the control sample may also contain the following alleles from the IL-1 (33221461) haplotype: allele 3 of the 222/223 marker (*130 mu PCR product), allele 3 of the gz5/gz6 marker (*88 mu PCR product), allele 2 of the -889 marker (lacks an Ncol site), allele 2 of the +3953 marker (contains a TaqI site), allele'l of the -511 marker (lacks a Bsu36I site), allele 4 of the gaat.p33330 marker (*201 mu PCR product), allele 6 of the Y31 marker (* 166 mu PCR product), allele 1 of the VNTR marker (412 bp PCR product).
  • alleles are known to be associated with a variety of inflammatory disorders, such as coronary artery disease, osteoporosis, nephropathy in diabetes mellitus, alopecia areata, Graves disease, systemic lupus erythamatosus, lichen sclerosis, ulcerative colitis, diabetic retinopathy, periodontal disease, juvenile chronic arthritis particularly chronic iridocychtis, psoriasis, insulin dependent diabetes in DR3/4 patients and other diseases with an IL-1 loci genetic component.
  • inflammatory disorders such as coronary artery disease, osteoporosis, nephropathy in diabetes mellitus, alopecia areata, Graves disease, systemic lupus erythamatosus, lichen sclerosis, ulcerative colitis, diabetic retinopathy, periodontal disease, juvenile chronic arthritis particularly chronic iridocychtis, psoriasis, insulin dependent diabetes in DR3/4 patients and other diseases
  • a disease-associated haplotype (the set of alleles in linkage disequilibrium) will allow the investigator to begin to determine which of the alleles are causative, rather than merely linked to a disease-causing allele.
  • This information can be used to design rational treatment approaches, including gene therapy and treatment with a variety of agents that modulate the activity of the proteins produced by the IL-1 gene cluster. It is also possible that multiple mutations might each partially contribute to disease states for diseases of complex origin. Thus, if the mutations are additive or synergistic, the detection of these mutations would indicate even higher risk for the disease.
  • the presence of disease-associated alleles in linkage disequilibrium will allow the diagnostic testing of more than one allele, which will help to eliminate the possibility of false positive results.
  • Techniques for determining the presence of particular alleles may be nucleic acid techniques based on size or sequence, such as restriction fragment length polymorphism (RFLP), nucleic acid sequencing, or hybridization.
  • RFLP restriction fragment length polymorphism
  • Amplification techniques are known to those of skill in the art and include cloning, polymerase chain reaction (PCR), polymerase chain reaction of specific alleles (PAS A), polymerase chain ligation. nested polymerase chain reaction, and the like. Amplification products may be assayed in a variety of ways, including size analysis, restriction digestion followed by size analysis, detecting specific tagged ohgonucleotide primers in the reaction products, allele-specific ohgonucleotide (ASO) hybridization, sequencing, hybridization, and the like.
  • PCR polymerase chain reaction
  • PAS A polymerase chain reaction of specific alleles
  • ASO allele-specific ohgonucleotide
  • PCR based detection means include multiplex amplification of a plurality of markers simultaneously. For example, it is well known in the art to select PCR primers to generate PCR products that do not overlap in size and can be analyzed simultaneously. Alternatively, it is possible to amplify different markers with primers that are differentially labeled and thus can each be detected. One means of analyzing multiple markers involves labeling each marker with a different fluorescent probe. The PCR products are then analyzed on a fluorescence based automated sequencer. Of course, hybridization based detection allows the differential detection of multiple markers.
  • Allele detection techniques may be protein based if a particular allele produces a protein with an amino acid variant. For example, epitopes specific for the amino acid variant can be detected with monoclonal antibodies. Likewise, it is possible to detect alleles if they are present in processed RNA by techniques that are known in the art.
  • kits for detecting a propensity for inflammatory disease in a patient.
  • the kits can be used pre- or post-symptomatically or prenatally.
  • the diagnostic kit may comprise one or more oligonucleotides capable of hybridizing to nucleic acid from the IL-1 gene cluster.
  • a number of assay formats are useful for genotyping using the provided oligonucleotides. The most common formats involve nucleic acid binding, such binding to filters, beads, or microtiter plates and the like. Techniques may include dot blots, RNA blots, DNA blots, PCR, RFLP, and the like.
  • the oligonucleotides may be a variety of natural and synthetic compositions such as synthetic oligonucleotides, restriction fragments, cDNAs, synthetic PNAs, and the like.
  • the assay may also employ labeled oligonucleotides to allow ease of identification in the assays. Examples of labels which may be employed include radiolabels, enzymes, fluorescent compounds, streptavidin, avidin, biotin, magnetic moieties, metal binding moieties, antigen or antibody moieties, and the like.
  • Oligonucleotides include the following:
  • ATGTATAGAATTCCATTCCTG SEQ ID NO. 1
  • CAGTGTGTCAGTGTACTGTT (SEQ ID NO. 14), CTCAGCAACACTCCTAT (SEQ ID NO. 15),
  • TGCAGACAGACGGGCAAAGT SEQ ID NO. 23
  • TTGTGGGGACCAGGGGAGAT SEQ ID NO. 24
  • the kit may also include DNA sampling means such as the AmpliCardTM (University of Sheffield, Sheffield, England S10 2JF; Tarlow JW, et al. J. of Invest. Dermatol 103:387-389
  • Another embodiment of the invention provides a method of identifying additional alleles in linkage with an IL-1 haplotype, for example the IL-1 (44112332) haplotype. Additional alleles from the IL-1 gene cluster can be identified by sequence analysis of this region of the DNA. Altematively, additional alleles can be identified by restriction enzyme analysis (for methods of identifying novel markers, see McDowell, et al, Br. J.
  • the invention is also directed to methods for identifying additional inflammatory disorders that are associated with alleles from an IL-1 haplotype. Groups of patients with and without disease are genotyped and compared. In this way it is possible to show that the haplotype is associated with new inflammatory disorders.
  • the following example illustrates embodiments of the invention, but should not be viewed as limiting the scope of the invention.
  • the primer sequences and fluorescent labels used in PCR amplification of markers were as in Table 2.
  • PCR products were examined by agarose gel electrophoresis and the remainder of the PCR products were pooled according to the intensity of ethidium bromide staining. 2 ⁇ l of the pool was analyzed on an ABI 373 A automated sequencer and allele sizes were determined using the Genescan and Genotyper software. Alleles were globally binned using a simple computer program and numbered in order of size.
  • Allele 1 produces 83 and 16 bp fragments. Allele 2 produces a 99 bp fragment.
  • Allele 2 produces a 304 bp fragment when digested with Aval and 190 and 114 bp fragments when digested with Bsu36I.
  • VNTR PCR products were sized by electrophoresis on 2% agarose gel at 90V for 45 minutes. Allele 1 has 4 repeats and the PCR product is 412 bp, allele 2 has 2 repeats and the PCR product is 240 bp, allele 3 has 3 repeats and the PCR product is 326 bp, allele 4 has 4 repeats and the PCR product is 498 bp, allele 5 has 6 repeats and the PCR product is 584 bp.
  • Intergenic distances were determined by estimation based on the insert sizes of relevant PAC clones from a contig spanning the IL-1 gene cluster (Nicklin, et al, Genomics 19:
  • Example 2 Method for Estimating Linkage Disequilibrium Because four of the markers studied herein are multiallelic, a preliminary analysis was carried out to determine which allelic combinations between pairs of loci contributed to the greatest disequilibrium, in order that the disequilibrium would not be masked when the alleles were grouped into biallelic systems.
  • the E.H. program of Xie and Ott (Handbook of Human Genetic Linkage, 1994, John Hopkins University Press, 188-98), incorporated by reference herein, was used to estimate haplotype frequencies under H 0 (no linkage) and H [ (allelic linkage allowed).
  • haplotype count the probability of each set was calculated and used as a "partial" count. In this way the ambiguous genotypes were also haplotype counted, and the total counts (ambiguous plus unambiguous) constituted the O' y 's used in ⁇ y . Once established, the magnitude and sign of the ⁇ 's were used to determine which allelic combinations showed greatest deviation from the null hypothesis of no association. This information was used to group alleles at the multiallelic loci into biallelic systems to enable efficient use of the E.H. program.
  • Example 3 Estimation of Linkage Disequilibrium in the I -1 Gene Cluster A number of biallelic and multiallelic markers in and around the IL-1 genes have been identified. However, the extent of linkage disequilibrium between the markers, and the prevalence of multimarker haplotypes in the general population have not until now been identified.
  • Figure 1 shows the relative positions of the 8 marker loci used in this study. DNA samples from 212 unrelated healthy volunteers were genotyped for each of these markers, and the resulting estimates of allele frequencies are shown in Table 4.
  • Table 6 shows the power to detect 50% D max for each locus combination, and the p values for each corresponding D.
  • D was calculated for all the comparisons involving 222/223 using two additional grouping strategies. The first of these was a "common allele versus the rest" approach, and the second was a grouping based on allele size, using the bimodal distribution of allele frequency versus size which was observed for all the multiallelic markers examined. The results of this analysis are shown in Table 7, where D values for the three grouping methods are compared. Table 7. D values for three methods of grouping alleles at the multiallelic marker loci
  • the method could be simplified, in a sufficiently large study, by just considering the unambiguous haplotypes when determining the grouping.
  • the determination of ⁇ y - uses the maximum amount of prior knowledge for the grouping of the multiallelic markers, and this may be the reason why disequilibrium between almost all pairwise combinations of markers was detected.
  • the two haplotypes containing all 8 markers, as well as other shorter haplotypes, are of particular interest since it is likely that particular combinations of alleles of the IL-1 genes may act in concert to determine an overall inflammatory phenotype.
  • An understanding of which markers are in strong linkage disequilibrium not only allows for more rational design of genetic studies but also may provide clues to disease mechanism.
  • Additional alleles may also be part of the IL-1 (44112332) haplotype. We have previously shown that 5 novel markers were associated with allele 2 of the VNTR marker of the
  • ILIRN gene (Clay, et al, Hum. Genet. 97: 723-6 (1996)). It is probable that these five alleles are in linkage disequilibrium, although confirmation by statistical analyses has not yet been performed.
  • the IL-1 (44112332) haplotype may also include these five markers.
  • Guasch found 3 additional alleles in ILIRN (Guasch, et al, Cytokine 8: 598-602 (1997)) which appeared at the same frequencies in a small sample (12 individuals).
  • One of the Guasch alleles (the Mspl allele) is the 8006 allele of the Clay study. Therefore, the additional two alleles by Guasch (Mwol and Sspl alleles) may be part of the IL-1 (4112332) haplotype discovered herein. However, this should be confirmed as described herein because the very small sample size may have produced misleading results.
  • the IL-1 (44112332) haplotype may contain the following alleles: allele 2 of the 1731 marker of the ILIRN gene (A at position 1731) allele 2 of the 1812 marker of the ILIRN gene (A at position 1812) allele 2 of the 1868 marker of the ILIRN gene (G at position 1868) allele 2 of the 1887 marker of the ILIRN gene (C at position 1887) allele 2 of the 8006 marker of the ILIRN gene (contains a Hpall or Mspl site) allele 2 of the 8061 marker of the ILIRN gene (lacks a Mwol site) allele 2 of the 9589 marker of the ILIRN gene (contains an Sspl site)
  • PCR primers may be used to amplify these alleles:
  • Example 4 The TT -1 (44112332) Haplotype is Associated with Diabetic Nephropathy
  • NIDDM non-insulin dependant diabetes melhtus
  • the IL-1 (44112332) haplotype was carried by 24 of 79 of the NIDDM nephropathy patients and 25 of 141 NIDDM without nephropathy patients. However, the second haplotype
  • the haplotype is associated with inflammatory disease.
  • Example 5 An TL-1 Haplotype is Associated with Inflammatory Disease This is a prophetic example. Other diseases are examined as per Example 4. The
  • IL-1 (44112332) haplotype is found to be associated with coronary artery disease, osteoporosis, nephropathy in diabetes mellitus, alopecia areata, Graves disease, systemic lupus erythematosus, lichen sclerosis and ulcerative colitis.
  • the IL-1 (33221461) haplotype is associated with periodontal disease, juvenile chronic arthritis, psoriasis, insulin dependant diabetes and diabetic retinopathy.
  • a patient with a family history of ulcerative colitis is genotyped for the presence of the IL-1 (44112332) haplotype. Genotyping is performed as in
  • Example 1 and the patient is determined to carry one or more alleles of the haplotype.
  • the patient is thus treated with IL-1 antagonists to prevent disease.
  • a second patient with a family history of coronary artery disease is genotyped at the
  • the patient is found to carry one or more alleles of the IL-1 (44112332) haplotype and be homozygous for the VNTR allele 2.
  • the patient is 5.4 times as likely to develop coronary artery disease as the general population and is treated vigorously to prevent disease.

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DE69841588T DE69841588D1 (de) 1997-05-29 1998-05-21 Vorhersage von entzündlichen krankeiten assoziert mit il-1 genlocus polymorphismen
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CN1177059C (zh) 2004-11-24
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US6268142B1 (en) 2001-07-31
US20080187920A1 (en) 2008-08-07
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US20020146700A1 (en) 2002-10-10
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AR016754A1 (es) 2001-08-01
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