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.
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.
Authors: S H Laval; A Timms; S Edwards; L Bradbury; S Brophy; A Milicic; L Rubin; K A Siminovitch; D E Weeks; A Calin; B P Wordsworth; M A Brown Journal: Am J Hum Genet Date: 2001-02-27 Impact factor: 11.025