INVESTIGATING THE GENETIC-BASIS FOR ANKYLOSING-SPONDYLITIS - LINKAGE STUDIES WITH THE MAJOR HISTOCOMPATIBILITY COMPLEX REGION

Objective. To assess the hypothesis that B27 or a gene(s) in close pro ximity (e.g., within or near the major histocompatibility complex [MHC ]) represents a disease-causing ankylosing spondylitis (AS) gene, and therefore contributes directly to the pathogenesis of this disorder. M ethods. MHC haplotypes were determined by both serologic and molecular analyses in 15 multiple-case AS families from Toronto and Newfoundlan d. Segregation of MHC haplotypes with AS within these families was exa mined by linkage and identity-by-descent analyses. Attributable risk e stimates for various genetic markers and for sex were calculated. Resu lts. Linkage analyses established significant linkage between AS and t he MBC, the maximal logarithm of odds (LOD) score being 3.48 at a reco mbination frequency (Theta) of 0.05. In a second analysis in which the population association of the MWC gene HLA-B27 with AS was taken into account, the maximal LOD score was 7.5 at Theta = 0.05. Identity-by-d escent analyses showed a significant departure from random segregation among affected avuncular (P < 0.05) and cousin (P < 0.01) pairs. The presence of HLA-B40 in HLA-B27 positive individuals increased the risk for disease more than 3-fold, confirming previous reports. Disease su sceptibility modeling suggested an autosomal dominant pattern of inher itance, with penetrance of approximately 20%. Conclusion. These data p rovide the first conclusive demonstration of linkage between the MHC r egion and AS, and confirm that genes within this region contribute dir ectly to the genetic susceptibility for AS.