Objective
Ankylosing Spondylitis (AS) and other spondylarthropathies (SPA) are the second most frequent cause of chronic inflammatory rheumatisms and represent a socio-economic burden. The genetic predisposition is strongly linked to the MHC complex HLA-B27 gene but other loci are also implicated. Infectious agents also play a role in the determination of these multifactorial disorders which still have to be clearly delineated.
The I objective of our project is to localize the susceptibility gene(s) other than HLA-B27 whether or not linked to the MHC region and thus:
1) to determine if susceptibility gene(s) other than B27, located in the MHC or in other loci of the genome are associated with these diseases and contribute to their etiology and pathogenesis;
2) to determine the genotype-phenotype relationships by investigating whether other cooperative / expression gene(s) modify the phenotype, and the exact role infectious agents play in AS and SPA. Multifactorial disease methodology will be used applying multipoint Affected Sib Pair (ASP) and Extended Family (EF) analyses and the Transmission / Disequilibrium Test (TDT). The project will thus comprise: 1- FAMILIAL COLLECTION: at least 200 affected sib pair families and 40 extended families, the minimum I family number required for the ASP analysis to be powerful enough, will be collected by the cooperation j between 8 European Member states; 450 simplex families will be identified for TDT analysis. Using a detailed chart all the enrolled persons will be examined by rheumatologists to ascertain disease diagnosis and severity, and to classify them as affected/unaffected according to the European Spondylarthropathy Study Group and Amor criteria. Blood samples obtained from each enrolled subject will be used to constitute collections of DNA, peripheral blood mononuclear cells, serum, and Iymphocytes from selected cases will be immortalized.
II- MOLECULAR GENETICS STUDY:
A) Search for the susceptibility and or cooperative / expression gene(s) in the MHC region of the genome by HLA Extended haplotype analyses with stratification respective to B27 presence and severity of the disease:
1) To revisit the role of HLA B27 and to identify the involvement of other MHC gene(s), B27 status will be assessed in all the enrolled persons using MHC extended haplotype linkage and association analyses.
This requires:
a) HLA class I serologic determination;
b) HLA B27 subtyping (9 known alleles);
c) HLA-DR, DP, DQ and DM alleles determinations by SSO (ASO) and/or PCR/RFLP;
d) TAP 1/2 and LMP 2/7 genes allele determination by SS0 (ASO) or ARMS-PCR;
e) MIC-A and MIC-B polymorphism investigation by PCR/RFLP and SSO(ASO);
f) TNF and IL6. HLA DNA typing will be performed in concentration with the Biomed-2 "HLA in Europe";
2) HLA-B27 gene (or other involved genes) function study : Search for self or non-self arthritogenic peptide(s) potentially triggers of SPA and T-cell repertoire analysis in SPA affected patients.
B) Systematic scanning of the Genome to search for other susceptibility and or cooperative / expression gene(s). According to MHC extended haplotype determination, other genes involved will be sought. ASP analysis will be performed on the first 100 multiplex families, and the results updated as the number of families grows. Taking into account the clinical status and concordance, HLA haplotypes and B27 positivity a multistep analysis will be used with 2 available overlapping fluorescent microsatellite panels covering all the genome with 7.5 cM total resolution. After checking informativity through simulation, classical linkage analysis will be used on the extended families with fluorescent markers. The region(s) of interest thus detected will be saturated with non fluorescent markers from the Genethon map.
C) Statistical Genetic analyses will be performed by statistician team using: the MAPMAKER/SIBS program package for ASP analyses; the S-LINK program; the 'LINKAGE' package (Lathrop Version 5.3); Association Analysis classical techniques and Relative Risk calculation (Woolf). Only an European transnational cooperation will allow inclusion of the required number of families and: satisfactory analysis of genetic diversity. Significant linkage or associations could thereby be identified and their significance tested in various European populations. The genetic data will be used for the immunopathology studies. More accurate diagnostic, risk assessment procedures and new therapeutic approach, with positive consequences for clinical practice, prevention, treatment and social cost can be expected which would improve European public health.
Keywords: Ankylosing Spondylitis, Spondylarthropathies, Genome, Genetic map, Genethon, DNA and Cell ,collections, HLA B27, HLA extended haplotypes, Affected Sib pair and Extended family analyses.
Fields of science (EuroSciVoc)
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CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health scienceshealth sciencespublic health
- natural sciencesbiological sciencesmolecular biologymolecular genetics
- natural sciencesbiological sciencesgeneticsDNA
- natural sciencesbiological sciencesbiochemistrybiomolecules
- natural sciencesbiological sciencesgeneticsgenomes
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Call for proposal
Data not availableFunding Scheme
CSC - Cost-sharing contractsCoordinator
75674 PARIS
France