The goal of this proposal is to define the genetic basis of ankylosing spondylitis (AS) susceptibility. This? project is centered around four hypotheses; 1) that the MHC contribution to the genetic basis of AS, though? primarily provided by HLA-B27, is augmented by other MHC influences that require novel approaches to? elucidate; 2) that the contribution of non-MHC genes, though vital, is sufficiently small to require large? sample sizes and confirmation in independent cohorts; 3) that these genetic factors interact with each other? in a complex manner to influence disease susceptibility; and 4) that rigid and consistent phenotypic? characterization is crucial to the success of any genetic study, particularly that of AS.
The specific aims of? this project are, therefore: 1. To establish a resource of U.S. AS cases and locale matched controls for? genemapping studies by increasing our resource of cases and controls up to a total of 1500 of each. 2. To? perform a genomewide scan of susceptibility to AS in 1000 British patients meeting modified New York? criteria for AS, and 3000 Controls. We will examine 675,000 SNP's using the 500K Affymetrix chip and a? 175K SNP chip from Perlegen in a group of 1,000 U.K. patients meeting the modified New York criteria for? A.S. compared with 3,000 U.K. controls for all the SNPs under consideration. 3. To confirm initial positive? findings fof the most significant 1.4% of the SNPs from the genomewide association study in 1500 U.S. AS? cases 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 to? date, and has a high likelihood of greatly increasing the proportion of the heritability of AS-susceptibility for? which genes have been identified. By encompassing the two largest cohorts of AS patients examined to? date, utilizing cutting edge technologies and analystic approaches, and careful phenotyping, we believe that? his study will produces major advances inour understanding of the genetic basis of AS.
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