Although HLA-B27 is regarded as an essential feature for the development of ankylosing spondylitis (AS), recent studies have implicated other genes and chromosomal regions, both inside and outside the major histo-compatibility complex (MHC), in the pathogenesis of the disorder. The entire MHC contribution has been calculated at only 31%. Linkage analysis of sib pairs from the United Kingdom has shown eight chromosomal regions, including the MHC, to have moderate evidence of linkage to AS. However, many genes are contained in these regions, and which are the actual disease susceptibility genes within these regions has not been established. Our hypothesis is that other genes interact with HLA-B27 to produce spondylitis.
The specific aims of this proposal, then, are: 1. To establish a consortium of investigators based at nine academic medical centers (the North American Spondylitis Consortium, or NASC), who will identify from their own spondylitis patient population families with two sibs concordant for AS (by modified New York criteria), as well as one unaffected sibling, and (when available) their parents. 2. To identify from the membership of the Spondylitis Association of America (SAA) similar families who are available for study. 3. To examine family members of patients with either AS or As associated with inflammatory bowel disease (IBD) by questionnaire for symptoms of inflammatory back pain, measurements of spinal mobility, and pelvic radiographs to confirm disease presence and to characterize the clinical features of AS, as well as to obtain blood samples from the above mentioned family members for genomic DNA extraction. 4. To carry out HLA-B27, B60 and HLA class II typing by DNA analysis in all family members in order to characterize the MHC class II contribution to predisposition to AS. 5. To localize relevant genes by whole genome scan of sib pairs concordant and discordant for AS in 400 Caucasian families. 6. To conduct microsatellite polymorphism analyses of non-MHC genes using multipoint analysis for fine mapping studies of genes linked to AS. 7. To study sequence variation of candidate genes to identify the mutations and genes involved in AS.
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