Hla‐dr/Dq/Dp Interactions in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is associated with the presence of particular HLA-DRB1 alleles. In order to characterize HLA-DQB1 and/or-DPB1 alleles that contribute to disease susceptibility besides HLA-DRB1 alleles, we have analysed the HLA-DRB1, -DQB1 and -DPB1 polymorphism in 84 RA patients and 135 controls. HLA typing for HLA-DRB1 and -DQB1 alleles was performed using sequence-specific primers in combination with sequence-based typing. HLA-DPB1 alleles were characterized by reverse dot-blot hybridization. Our data confirm the predominant role of the (Q)R/KRAA sequence from AA position 70-74 of the HLA-DRB chain for disease susceptibility. In particular, the lysine (K) substitution at position 71 was highly significantly associated with RA. Analysis of the DQB1 locus revealed no association with RA when linkage disequilibrium between HLA-DRB1 and -DQB1 alleles was considered. In contrast, we observed an increased frequency of HLA-DPB1*0401 among (Q)R/KRAA-positive patients. (Q)R/KRAA-negative RA patients exhibited an overrepresentation of HLA-DPB1*0201 and HLA-DPB1*0601. Rheumatoid factor (RF) production correlated with the presence of the disease-associated (Q)R/KRAA amino acid cassette of the HLA-DRB chain. When HLA-DPB1 allele frequencies were compared between RF-positive and RF-negative RA patients, we observed an increased frequency of HLA-DPB1*0401 among RF-positive RA patients and HLA-DPB1*0201 among RF-negative patients. These results suggest that besides the predominent role of HLA-DR molecules in RA, HLA-DP molecules may have an influence on disease susceptibility and could modulate disease progression. HLA-DPB1*0401 may function in addition to HLA-DRB1*04, whereas HLA-DPB1*0201 and -DPB1*0601 may represent additional risk factors among (Q)R/KRAA-negative RA patients.

HLA-DPB1-COL11A2 and three additional xMHC loci are independently associated with RA in a UK cohort

“…[18][19][20][21][22][23][24][25][26] Our result in a UK cohort together with previous studies in Swedish and North American populations 14,15 provides strong evidence that HLA-DPB1-COL11A2 is a genuine RA risk locus independent of HLA-DRB1 and the rest of the xMHC region. Several SNPs were found to be associated with RA in this intergenic region, distributed in two different LD blocks.…”

Anti‐Caspase‐8 Autoantibody Response in Silicosis Patients is Associated with HLA‐DRB1, DQB1 and DPB1 Alleles

“…Other autoimmune diseases such as RA 18,19) or IDDM 20) are reported to link to DR4. The predominant role of the (Q)R/KRAA sequence at position 70-74 of the DRB1 chain, in particular the lysine (K) substitution at position 71 as in DRB1*0406, has been reported to be highly associated with RA susceptibility 9,10) . It seems that the antigen presentation of caspase-8 through HLA-DRB1 takes the same process as in the case of RA or IDDM.…”

“…Seidl et al 10) described HLA-DPB1*0401 and *0601 alleles as risk factors among RA patients. This suggests that antigen presentation of the caspase-8 molecule takes also the similar process by HLA-DPB1 as in the case of RA.…”

“…In this study, we analyzed the correlation between anticaspase-8 autoantibody response and HLA class II alleles in silicosis patients using a PCR restriction fragment length polymorphism (PCR-RFLP) method in order to establish whether specific alleles might in part explain disease susceptibility, since autoimmune responses such as the production of autoantibodies against pancreas islets in insulin dependent diabetes mellitus (IDDM ) 8) , rheumatoid factor production 9) or susceptibility to rheumatoid arthritis (RA) 10) , anti-scl-70 (topoisomerase I) antibody production in SSc 11) , or SSA production in Sjogren's syndrome 12) have been reported to be associated with specific HLA class II alleles. We now report the association of anti-caspase-8 antibody response with HLA class II alleles.…”

Effect of swine leukocyte antigen‐DQA gene variation on diarrhea in Large White, Landrace, and Duroc piglets

“…haplotype or phase of multiple single nucleotide polymorphisms (SNPs)] would be ideal for the study of gene–disease association when compared to work on single‐locus alleles (Seidl et al . ; Morris & Kaplan ). For example, multiple SNPs within SLA‐DRA exon coding regions are associated with diarrhea resistance in Large White, Landrace and Duroc piglets (Yang et al .…”