Investigating the genetic basis for ankylosing spondylitis. Linkage studies with the major histocompatibility complex region

Abstract

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 diseasecausing 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 multiplecase AS families from Toronto and Newfoundland. Segregation of MHC haplotypes with AS within these families was examined by linkage and identity-bydescent analyses. Submitted for publication October 4, 1993; accepted in revised form February 27, 1994. linkage between AS and the MHC, the maximal logarithm of odds (LOD) score being 3.48 at a recombination frequency (0) 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 0 = 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.

The effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis

“…Nonetheless, we have shown a weak but significant increase in disease risk in B27-positive, DR1-positive individuals compared with ethnically matched B27-positive controls. The positive association was stronger among DR1 homozygotes than heterozygotes, supporting the notion that this is a true-positive association rather than a manifestation of linkage disequilibrium with B27, since homozygosity for B27 is not thought to increase disease susceptibility (20)(21)(22). It is Possible that a B27;DRl haplotype bearing a further disease-causing gene was present in this population, and that B27 and DR1 were merely markers for this gene.…”

Dose reduction of recombinant human tumor necrosis factor inhibitors (etanercept) can be effective in ankylosing spondylitis patients with synovitis of the hip in a Chinese population

“…3 The etiology of AS is still largely unknown, however a number of linkage studies have implicated an interaction of environmental insults and genetic susceptibility like HLA-B27. 4 About 20% of patients with AS are involved in the hip and shoulder arthritis always Dose reduction of recombinant human tumor necrosis factor inhibitors (etanercept) can be effective in ankylosing spondylitis patients with synovitis of the hip in a Chinese population portend a worse outcome. 5 Thus, targeting the specific inflammatory processes of the disease may essentially influence disease progression.…”

Genetics in Ankylosing Spondylitis – Beyond HLA-B*27

“…Genetic factors contribute with more than 90% for the susceptibility risk to AS being the MHC region, in particularly HLA-B27, the main contributor (Brown, et al, 1996). This evidence is supported by studies using familial cohorts; segregation and twin studies (Brown, et al, 1997;Jarvinen, 1995;Rubin, et al, 1994).…”