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WO2004097045A1 - Methode diagnostique pour la spondylite ankylosante - Google Patents

Methode diagnostique pour la spondylite ankylosante Download PDF

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Publication number
WO2004097045A1
WO2004097045A1 PCT/GB2004/001905 GB2004001905W WO2004097045A1 WO 2004097045 A1 WO2004097045 A1 WO 2004097045A1 GB 2004001905 W GB2004001905 W GB 2004001905W WO 2004097045 A1 WO2004097045 A1 WO 2004097045A1
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WIPO (PCT)
Prior art keywords
polymorphism
subject
region
polymorphisms
seronegative spondyloarthropathy
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PCT/GB2004/001905
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English (en)
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Matthew Arthur Brown
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Isis Innovation Limited
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Publication of WO2004097045A1 publication Critical patent/WO2004097045A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • This invention relates to the identification of genetic markers associated with ankylosing spondylitis (AS).
  • AS ankylosing spondylitis
  • this invention relates to a diagnostic test for determining whether a patient is genetically predisposed to AS.
  • Ankylosing spondylitis is the prototype for a variety of diseases known collectively as the seronegative spondyloarthropathies (Khan, M.A. Rheum Dis Clin ⁇ / yAmer 18:1-10 (1992)).
  • Other diseases in this group include Reiter's syndrom (RS), reactive arthritis, and other inflammatory diseases such as psoriatic arthritis, arthritis associated with inflammatory bowel disease, and acute anterior uveitis (AAU).
  • the seronegative spondyloarthropathies are characterised in the early stages by a chronic inflammatory infiltrate containing lymphocytes and plasma cells and later by fibroblastic proliferation, leading to formation of scar tissue as a chronic healing process ensues.
  • the scarring results in the ankylosis of joints which may then undergo enchondral ossification of non-inflamed articular cartilage.
  • the tendency of the fibrous tissue to ossify produces radiographic changes such as paravertebral ossification, bamboo spine, and plantar spurs.
  • Inflammation which begins within the cartilage can involve the periosteum, ligaments, joint capsules, annulus of the interverbral disks, synovium, as well as the uveal tract and aortic wall.
  • the main extra-skeletal manifestations include ulceris and chronic aortitis leading to aortic regurgitation.
  • atrioventricular conduction abnormalities can also occur requiring valve replacement or pacemaker treatment, respectively.
  • HLA-B27 is a major histocompatibility complex (MHC) antigen strongly associated with spondyarthropathy.
  • HLA-B27 may be a factor that influences susceptibility to Spondyarthropathy (97% of patients with Spondyarthropathy carry HLA-B27)
  • conventional HLA B27 testing is not a useful screening or diagnostic test, because the antigen is present in 6-9% of the UK Caucasian population
  • IL-1 is a primary cytokine implicated in mediating chronic and acute inflammatory diseases
  • the IL-1 family consists of two functionally similar molecules, IL-1 ⁇ and IL-1 ⁇ , encoded by separate genes IL-1 A and IL-1 B and an IL-1 receptor antagonist IL-1 RA, encoded by IL-1 RN, which is an anti- inflammatory nonsignal ng molecule that competes for receptor binding with IL- 1 ⁇ and IL-1 ⁇
  • IL-1 RN an anti- inflammatory nonsignal ng molecule that competes for receptor binding with IL- 1 ⁇ and IL-1 ⁇
  • McGarry et al , Rheumatology, 2001 , 40 1359-1364 discloses a link between a polymorphism within the interleukin 1 receptor antagonist (IL-1 Ra) gene and AS Polymorphic sites within the IL-1 family were examined, including the 86-base pair variable number tandem repeat within intron 2 of the IL-1 Ra gene (or chromosome 6) and polymorphisms at positions -889 in the IL1 ⁇ gene and -511 in the IL-1 ⁇ gene The authors concluded that there were no significant differences at the polymorphic alleles in the IL-1 ⁇ and IL-1 ⁇ genes, but that there was a significant association between AS and patients carrying the polymorphism in allele 2 of the IL-1 RA Van der Paardt et al, Rheumatology, 2002, 41 1419-23 studied IL1 B-511 and the IL1 RA VNTR, and reported association of the allele 2 of the IL1 RA VNTR with AS, but not of the
  • the present invention is based on the finding that polymorphisms within genes in the ⁇ nterleuk ⁇ n-1 gene region of chromosome 2 are associated with AS
  • a method for detecting whether a subject has or is genetically predisposed to a seronegative spondyloarthropathy comprises determining the presence in the subject of a genetic polymorphism within the interleukin 1 gene region of chromosome 2 in the region extending from the beginning of IL-1 A to the beginning of IL-1 RN in a genetic sample obtained from a subject
  • an isolated polynucleotide that is useful for diagnosing whether a subject has or is predisposed to a seronegative spondyloarthropathy, comprises at least 15 contiguous bases derived from the interleukin 1 gene region of chromosome 2, extending from base 113621783 to base 11397071 1 , or its complement
  • a diagnostic kit comprises a polynucleotide as defined above Description of the Invention
  • the present invention utilises known methods of genetic analysis to determine whether a particular subject has, or is predisposed to, a seronegative spondyloarthropathy, e g AS
  • genetic predisposition refers to an increased likelihood that a given subject has or is likely to develop a seronegative spondyloarthropathy, given the presence of a particular genomic sequence (polymorphism)
  • seronegative spondyloarthropathy is intended to refer to the related group of diseases, such as, Ankylosing Spondylitis (AS), Reiter's syndrome (RS), reactive arthritis, and other inflammatory diseases such as pso ⁇ atic arthritis, arthritis associated with inflammatory bowel disease, chronic juvinyl arthritis, Acute Anterior Uveitis (AAU), and the like
  • AS Ankylosing Spondylitis
  • RS Reiter's syndrome
  • reactive arthritis and other inflammatory diseases such as pso ⁇ atic arthritis, arthritis associated with inflammatory bowel disease, chronic juvinyl arthritis, Acute Anterior Uveitis (AAU), and the like
  • allele is used herein to refer to variants of a nucleotide sequence.
  • a biallelic polymorphism has two forms; designated herein as “allele 1 " and "allele 2". Diploid organisms may be homozygous or heterozygous for an allelic form.
  • haplotype is used herein to refer
  • polymorphism refers to the occurrence of two or more alternative genomic sequences or alleles between or among different genomes or subjects.
  • a single nucleotide polymorphism is a single base pair change.
  • a SNP is the replacement of one nucleotide by another nucleotide at the polymorphic site. Deletion of a single nucleotide, or insertion of a single nucleotide, also gives rise to single nucleotide polymorphisms.
  • the polymorphisms associated with a predisposition to seronegative spondyloarthropathy are found within the region from the IL-1 A gene to the beginning of the IL-1 RN gene in the interleukin 1 region of chromosome 2. This region extends from base 113621783 to 113970711 from the P-telomere of chromosome 2, numbered according to the UCSC Genome Browser July 2003 Freeze (www.genome.ucsc.edu). This region contains the genes listed in Table 1.
  • SNPs Single nucleotide polymorphisms
  • haplotypes Single nucleotide polymorphisms
  • the haplotypic associations are stronger than the associations of individual SNPs, suggesting either that there is an interaction between SNPs to cause the disease, or that the disease causing SNP lies on the haplotypes
  • SNPs found within the defined region may be used as a marker to determine the predisposition of a subject to a seronegative spondyloarthropathy disease, specific SNPs are identified in Table 2 Table 2
  • the reference to “ref snpid” refers to the database number given on the NCBI SNP database (http://www.ncbi.nlm.nih.gov/SNP/).
  • the database is publicly accessible and so the specific polymorphisms can be identified for each gene.
  • the column referred to as "allele” shows the single nucleotide substitution that characterises the SNP.
  • Table 3 shows preferred SNP combinations. In a preferred embodiment, one or more of these combinations of SNPs are determined, in orderto diagnose the susceptibility of a subject to a seronegative spondyloarthropathy, e.g. AS. Table 3: combination of polymorphisms
  • Haplotype Combination refers to the allele associated with each haplotype; 1 refers to the dominant allele, 2 refers to the recessive allele.
  • PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism
  • LCR ligase chain reaction
  • SSP Sequence Specific Primers
  • polynucleotide/hybndisation probes will usually comprise the polymorphic site, e g the SNP
  • the polynucleotides/hyb ⁇ disation probes may be detectably labelled, e g fluorescently labelled, using methods and labels known in the art, e g as used in the detection methods referred to above
  • the polynucleotides/hybndisation probes may be immobilised to a support surface, for use in a diagnostic assay
  • Suitable support materials are known in the art and include, ceramics, plastics, glass and silicon materials
  • Methods for immobilising polynucleotides to a support material are also known in the art
  • Polynucleotide array technology (DNA chips) are suitable for use in the invention, for screening of biological samples
  • Arrays that include the desired immobilised polynucleotides can be produced on a customised basis by various companies, including HySeq
  • the arrays employ immobilised polynucleotide probes that are complementary to target sequences from a biological sample (e g from a subject)
  • the target sequence will include a polymorphism as disclosed herein
  • the polynucleotides to be used as probes in a diagnostic method will usually complete at least an 8, 10, 15, 20 or 50 consecutive nucleic acid sequence derived from the defined IL-1 region, in particular derived from any of the genes identified in Table 1 , and most preferably derived from the polymorphic sites disclosed herein
  • Polynucleotides may also be designed to act as primers to amplify polynucleotides that may comprise a polymorphism
  • LOD logarithm of odds
  • SNPs in the genes IL-1 F7, IL-1 F9, IL-1 F6, IL-1 F8, IL-1 F5 and IL- 1 F10 were genotyped Extension Reactions (hME reactions) were designed using SpectroDESIGNER, Sequenom's assay design software, amplicon size containing the polymorphic site was set at 70-150bp and the mass of the extended primer within the mass range of 5000 - 8500 Da
  • SNPs were grouped according to termination mix, with all extension primers and possible extension products differing by a minimum of 50Da 5 ⁇ l PCR reactions were generated using 16mM (NH 4 ) 2 SO 4 , 67mM T ⁇ s-HCI (pH 8 8) 0 01 % Tween-20, 1 5mM MgCI 2 0 4mM dNTPs, 0 5 ⁇ M primers, Taq and 50ng DNA, and the PCR conditions 96°C 1 minute, 5 cycles 94
  • Unincorporated dNTPs from amplification products were removed using shrimp alkaline phosphatase (SAP).
  • SAP shrimp alkaline phosphatase
  • the extension reaction was performed using hME Termination mix 5.4 ⁇ M extension primer and 0.576 units MassEXTEND enzyme (thermosequenase).
  • the hME cocktail was transferred into SAP-cleaned PCR plates prior to cycling at 94°C for 2 minutes followed by 55 cycles of 94°C for 5 seconds, 52°C for 5 seconds and 72°C for 5 seconds followed by a 4°C soak.
  • SpectroCLEAN resin was used to remove excess ddNTPs and dNTPs by adding resin directly to the extension products, vortexing for 20 minutes then centrifuging for 5 minutes to pellet the resin.
  • the products were then spotted onto a SpectroCHIP and the chip was read in a Bruker Biflex III Mass Spectrometer system. Data were analysed on SpectroTYPER.
  • SNaPshot was used to genotype the IL-1A(-889) (rs1800587) polymorphism with forward and reverse primers 5'- GGGAACCCAAAACATTCATT-3'(SEQ ID No 1 ), 5'- CAGTGGCTAAGTTTGGGAAT-3'(SEQ ID No 2) and extension primer, 5'- CATTGAAGGCTCATATGTAAAAATCCATGGC-3'(SEQ ID No 3).
  • An initial 20 ⁇ l PCR reaction was carried out using 10mM Tris HCI pH8.3, 50mM KCI, 2.5mM MgCI 2 , 50 ⁇ M dNTPs, 0.2 ⁇ M oligonucleotide primers, 1 unit Taq polymerase (Taq Gold, Applied Biosystems) and 30ng DNA.
  • a touch down PCR program was used comprising 96°C for 12 minutes followed by 5 cycles, each decreasing by 2.5°C, of, 95°C for 30 seconds, 63-55.5°C for 30 seconds and 72°C for 30 seconds, followed by 20 cycles of 94°C for 30 seconds, 53°C for 30 seconds and 72°C for 30 seconds. A final extension of 72°C for 5 minutes and 4°C for 15 minutes.
  • Excess primers and dNTPs were removed by digestion at 37°C for 1 hour with Shrimp Alkaline Phosphatase (SAP) and Exonuclease I in a 20 ⁇ l reaction mix of 20mM Tris-HCI pH8, 10mM MgCI2, 1.5 units SAP, 1 unit Exol and 10 ⁇ l PCR product.
  • the 10 ⁇ l primer extension reaction consisted of 5 ⁇ l SNaPshot (Applied Biosystems) reaction mix, 3 ⁇ l post-digest PCR product and 2 ⁇ M extension primer. Extension was carried out through 25 cycles of 96°C for 10 seconds, 50°C for 5 seconds and 60°C for 30 seconds followed by 4°C for 15 minutes.
  • PCR products were digested accordingly with the appropriate enzymes, also listed in Table 6 and resultant products separated on ethidium bromide stained agarose gels, visualised by UV light PCR was also carried out for the IL-1 RN 46bp VNTR using the assigned primers in Table 6 and products were visualised by UV imaging of ethidium bromide stained 2% agarose gels Statistical analysis
  • Table 6 relates to the data on single marker case-control comparisons The P-values indicated in the shaded areas are statistically significant
  • Table 7 shows the within-family data In the individual columns, "Analyse” represents the single marker lod score (lod>3 6 occurs once by chance per 20 whole genome screens), “Transmit” represents the single marker test of association in the presence of linkage, where the P-value reflects associations only in this analysis, “2-marker Transmit” reflects the association of haplotypes of two adjacent markers consisting of the marker indicated on that row and the marker directly below Results are in the format giving the haplotype of alleles followed by a P-value For example, 2 1 001 means that the haplotype had allele 2 at marker 1 , allele 1 at marker 2, and P-value 0 001 The "3-marker Transmit” column is the same as for the 2-marker column except for 3 markers The "global P-value” reflects the overall association for that marker or combination of markers

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Abstract

La présente invention concerne une méthode in vitro permettant de détecter si un sujet souffre d'une spondylarthropathie séronégative ou présente une prédisposition à une spondylarthropathie séronégative, consistant à détecter la présence d'un polymorphisme génétique dans la région du gène de l'interleukine-1 du chromosome 2, allant de la base 113621783 à la base 113970711 à partir du télomètre P.
PCT/GB2004/001905 2003-05-01 2004-05-04 Methode diagnostique pour la spondylite ankylosante WO2004097045A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2162554A1 (fr) * 2007-05-31 2010-03-17 The University Of Queensland Marqueurs de diagnostic pour une spondylarthrite ankylosante et leurs utilisations

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5942390A (en) * 1996-01-12 1999-08-24 Cedars-Sinai Medical Center Method of diagnosing predisposition for ulcerative colitis in Jewish population by detection of interleukin-1 receptor antagonist polymorphism

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US5942390A (en) * 1996-01-12 1999-08-24 Cedars-Sinai Medical Center Method of diagnosing predisposition for ulcerative colitis in Jewish population by detection of interleukin-1 receptor antagonist polymorphism

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BIOQUE G. ET AL: "EVIDENCE FOR GENETIC HETEROGENEITY IN IBD: 1. THE INTERLEUKIN-1 RECEPTOR ANTAGONIST IN THE PREDISPOSITION TO SUFFER FROM ULCERATIVECOLITIS", EUROPEAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, vol. 8, no. 2, 1996, pages 105 - 110, XP001025574 *
DI GIOVINE F.S. ET AL.: "Single base polymorphism at -511 in the human interleukin-1 beta gene (IL1 beta).", HUMAN MOLECULAR GENETICS, vol. 1, no. 6, September 1992 (1992-09-01), pages 450, XP002077315, ISSN: 0964-6906 *
KHAN M.A.: "AN OVERVIEW OF CLINICAL SPECTRUM AND HETEROGENEITY OF SPONDYLOARTHROPATHIES", RHEUMATIC DISEASE CLINICS OF NORTH AMERICA, vol. 18, no. 1, 1992, pages 1 - 10, XP009034561, ISSN: 0889-857X *
MCGARRY F. ET AL.: "A polymorphism within the interleukin 1 receptor antagonist (IL-1Ra) gene is associated with ankylosing spondylitis", RHEUMATOLOGY (OXFORD), vol. 40, no. 12, December 2001 (2001-12-01), pages 1359 - 1364, XP002290518, ISSN: 1462-0324 *
NICKLIN M.J.H. ET AL.: "A Sequence-Based Map of the Nine Genes of the Human Interleukin-1 Cluster", GENOMICS, ACADEMIC PRESS, SAN DIEGO, US, vol. 79, no. 5, May 2002 (2002-05-01), pages 718 - 725, XP004465144, ISSN: 0888-7543 *
VAN DER PAARDT M. ET AL.: "Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in ankylosing spondylitis.", RHEUMATOLOGY (OXFORD), vol. 41, no. 12, December 2002 (2002-12-01), pages 1419 - 1423, XP009034658, ISSN: 1462-0324 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2162554A1 (fr) * 2007-05-31 2010-03-17 The University Of Queensland Marqueurs de diagnostic pour une spondylarthrite ankylosante et leurs utilisations
EP2162554A4 (fr) * 2007-05-31 2010-07-28 Univ Queensland Marqueurs de diagnostic pour une spondylarthrite ankylosante et leurs utilisations

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