Objective: To assess the hypothesis that B27 or a gene(s) in close proximity (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.
Methods: MHC haplotypes were determined by both serologic and molecular analyses in 15 multiple-case AS families from Toronto and Newfoundland. Segregation of MHC haplotypes with AS within these families was examined by linkage and identity-by-descent analyses. Attributable risk estimates for various genetic markers and for sex were calculated.
Results: Linkage analyses established significant linkage between AS and the MHC, the maximal logarithm of odds (LOD) score being 3.48 at a recombination frequency (O) of 0.05. In a second analysis in which the population association of the MHC gene HLA-B27 with AS was taken into account, the maximal LOD score was 7.5 at O = 0.05. Identity-by-descent 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 susceptibility modeling suggested an autosomal dominant pattern of inheritance, with penetrance of approximately 20%.
Conclusion: These data provide the first conclusive demonstration of linkage between the MHC region and AS, and confirm that genes within this region contribute directly to the genetic susceptibility for AS.