The goal of this proposal is to define the genetic basis of ankylosing spondylitis (AS) susceptibility. Thisproject is centered around four hypotheses; 1) that the MHC contribution to the genetic basis of AS, thoughprimarily provided by HLA-B27, is augmented by other MHC influences that require novel approaches toelucidate; 2) that the contribution of non-MHC genes, though vital, is sufficiently small to require largesample sizes and confirmation in independent cohorts; 3) that these genetic factors interact with each otherin a complex manner to influence disease susceptibility; and 4) that rigid and consistent phenotypiccharacterization is crucial to the success of any genetic study, particularly that of AS.
The specific aims ofthis project are, therefore: 1. To establish a resource of U.S. AS cases and locale matched controls forgenemapping studies by increasing our resource of cases and controls up to a total of 1500 of each. 2. Toperform a genomewide scan of susceptibility to AS in 1000 British patients meeting modified New Yorkcriteria for AS, and 3000 Controls. We will examine 675,000 SNP's using the 500K Affymetrix chip and a175K SNP chip from Perlegen in a group of 1,000 U.K. patients meeting the modified New York criteria forA.S. compared with 3,000 U.K. controls for all the SNPs under consideration. 3. To confirm initial positivefindings fof the most significant 1.4% of the SNPs from the genomewide association study in 1500 U.S. AScases and locale matched controls. 4. To investigate the role of gene-gene interaction in AS-susceptibility.This will be the largest and most comprehensive study of the genetic basis of AS susceptibility undertaken todate, and has a high likelihood of greatly increasing the proportion of the heritability of AS-susceptibility forwhich genes have been identified. By encompassing the two largest cohorts of AS patients examined todate, utilizing cutting edge technologies and analystic approaches, and careful phenotyping, we believe thathis study will produces major advances inour understanding of the genetic basis of AS.
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