FAMILY STUDIES OF THE GENETICS OF ANKYLOSING SPONDYLITIS

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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 histocompatibility complex (MHC), in the pathogenesis of the disorder. The entire MHC contribution has been calculated at only 31 percent. 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. Thus, the specific aims of this proposal are: 1) to establish a consortium of investigators with a recent record of clinical or genetic research in AS (and hence established patient cohorts) based at 10 academic medical centers throughout North America (the North American Spondylitis Consortium-NASC) in order to identify from their cohorts families with at least two siblings fulfilling the modified New York criteria for AS; 2) from the membership of the Spondylitis Association of America (SAA), to identify similarly affected families and verify the diagnoses in both groups by questionnaire, medical record review and pelvic radiographs; 3) to collect 50 ml of blood from affected and unaffected sib pairs and, when available, both their parents in order to establish a bank of sera, genomic DNA and frozen lymphocytes from these 400 families; 4) to characterize the MHC contribution to predisposition to AS by DNA typing for HLA-B27 alleles, B60 and HLA-DRB1, DQA1 and DQB1 alleles; 5) to conduct a genome wide search using closely spaced microsatellite markers in sib pairs concordant and discordant for AS in the 400 Caucasian families; 6) to conduct microsatellite polymorphism analyses of non-MHC genes using multipoint analyses for fine mapping studies of genes linked to AS using transmission disequilibrium testing (TDT); and finally, 7) to study sequence variation of three to four candidate genes in 25 AS patients and 25 controls to identify the mutations an disease-relevant polymorphisms involved in AS.