HLA haplotypes and susceptibility to rheumatoid arthritis

Abstract

Our aim was to examine, using microsatellite (ms) markers, the contribution of the telomeric part of the HLA region to rheumatoid arthritis (RA) predisposition in the Spanish population. We have looked at the distribution of DQB1, DRBI and five ms loci (D6S1014, D6S273, D6STNFa, MIB and C1-2-5) within the HLA region in 147 Spanish RA patients and 202 control subjects. A total of 19 conserved ms configurations were observed, twelve of them in linkage disequilibrium with particular DQB1-DRB1 haplotypes. Interestingly, haplotype c1 (DQB1*0201-DRB1*0301-D6S1014*143-D6S273*139-D6STNFa*99-MIB*350-C1-2-5*196) was significantly associated with RA predisposition. As part of this haplotype, the MIB*350 allele was found to be a risk factor independently of the RA-predisposing haplotypes. The present results along with data from others prove the existence of a second predisposing locus located inside the MHC region, and suggest that might be located within the TNFa-HLA-B region.

Genetics of rheumatoid arthritis: Is there a pattern predicting extraarticular manifestations?

“…An association between certain TNFα microsatellite markers and susceptibility to RA, independent of RA‐associated haplotypes, has been found in most (104–108), but not all, studies (109). Although microsatellite markers do not seem to affect disease severity by themselves, interactions between the markers TNFa6 (110) and TNFa11 (111) and SE genotypes have been reported to be associated with radiographic damage and disability.…”

Evidence for a novel rheumatoid arthritis susceptibility locus on chromosome 6p

“…These observations indicate that this genomic region may harbor further RA susceptibility genes, in addition to the HLA–DRB1 locus. Evidence in support of this hypothesis has accumulated from several recent studies demonstrating the independent association of non‐HLA MHC loci with RA (12–15), including identification of the IκB‐like protein as an independent disease susceptibility gene (16).…”

Persistent arthritis in Borrelia burgdorferi–infected HLA–DR4–positive CD28‐negative mice post–antibiotic treatment

“…Treatment refractory Lyme arthritis patients have a high frequency of HLA-DR4-related alleles compared to the ones that are treatment responsive (1, 3, 4). Interestingly, the same HLA-DR alleles have also been associated with susceptibility to RA (40, 41). Our murine studies indicate that the presence of HLA-DR4 or a related allele accentuates persistent Lyme arthritis post antibiotic treatment, since a significant fraction of antibiotic treated DR4 +/+ CD28 −/− MHC-II −/− mice, but none of the CD28 −/− mice, showed persistent joint inflammation after antibiotic treatment.…”