Influence of the HLA-DRB1 locus on susceptibility and severity in rheumatoid arthritis

Abstract

We examined HLA-DR genotype risk in 288 patients with rheumatoid arthritis who were carefully categorized for disease severity. Five hundred ethnically-matched bone-marrow donors were controls. A hierarchy of positive allelic associations was noted with DRB1*0401 (p < 10(-38), *0404,8 (p < 10(-43), *0405 (p < 10(-8), *10 (p < 10(-3) and *0101,2 (p < 10(-2), while DRB1*0403 was negatively associated (p = 0.02). The DRB1 genotype relative risks (and 95% CIs) for RA were: *0404,5,8/*0404,5,8 = 36.2 (15-87), *0401/*0404,5,8 = 31.3 (18-55), *401/*0401 = 18.8 (11-35), *0101,2/*0404,5,8 = 6.0 (2-14), *0101,2/*0401 = 6.4 (3-12), *0101,2/*0101,2 = 1.3 (0.3-6), *10/*0404,5,8 = 27.8 (5-148), *10/*0401 = 20.8 (5-89), *10/*0101,2 = 22.3 (5-96), *0404,5,8/DRX = 5.0 (3-8), *0401/DRX = 4.7 (3-7), *0101,2/DRX = 2.3 (1.4-4), *10/DRX = 3.4 (0.8-14). No significant correlation of DRB1 genotypes was found with severity of RA as judged by nodules or articular erosions.

Specific combinations of HLA-DR2 and DR3 class II haplotypes contribute graded risk for disease susceptibility and autoantibodies in human SLE

“…Homozygosity for DRB1*0401 and heterozygosity for DRB1*0401/ DRB1*0404 is associated with an increased risk for rheumatoid arthritis. 41 Heterozygosity for DR3/DR4 is strongly enriched in type 1 diabetes, whereas DR2 homozygosity shows strong association in multiple sclerosis. 42,43 Of interest, early studies suggested the possibility of genetic complementation between DR2/DQ6 and DR3/DQ2 haplotypes in susceptibility to lupus, as well as to Sjogren's syndrome, a disease related to SLE characterized by a high incidence of antinuclear antibodies.…”

RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response

“…[41][42][43][44][45][46][47][48][49][50] In view of the linkage disequilibrium between DRB1*0401 and the RAGE 82S allele, it will be interesting to specifically test whether DR4 haplotypes containing the RAGE 82S allele have an influence on disease progression and outcome. By analogy with our observations in cultured CHO and human mononuclear cells, we speculate it may be possible to identify a subset of subjects with RA particularly vulnerable to the sequelae of heightened production/activation of proinflammatory mediators.…”

High-density SNP analysis of 642 Caucasian families with rheumatoid arthritis identifies two new linkage regions on 11p12 and 2q33

“…5 Consistent associations clearly implicate a role of the major histocompatibility complex (MHC) in risk for RA. 6 Indeed, based on previous linkage results, the MHC region makes the largest single contribution (l s B1.8) to disease susceptibility. 7,8 A set of alleles at the DRB1 locus, many of which share a common polymorphic sequence, the 'shared epitope' (SE), 9 explain a large portion, but not all, [10][11][12] of the genetic risk within the MHC.…”