Objective. To identify additional variants in the major histocompatibility complex (MHC) region that independently contribute to risk in 2 disease subsets of rheumatoid arthritis (RA) defined according to the presence or absence of antibodies to citrullinated protein antigens (ACPAs).Methods. In a multistep analytical strategy using unmatched as well as matched analyses to adjust for HLA-DRB1 genotype, we analyzed 2,221 single-nucleotide polymorphisms (SNPs) spanning 10.7 Mb, from 6p22.2 to 6p21.31, across the MHC. For ACPA-positive RA, we analyzed samples from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) and the North American Rheumatoid Arthritis Consortium (NARAC) studies (totaling 1,255 cases and 1,719 controls). For ACPA-negative RA, we used samples from the EIRA study (640 cases and 670 controls). Plink and SAS statistical packages were used to conduct all statistical analyses.Results. A total of 299 SNPs reached locus-wide significance (P < 2.3 ؋ 10 -5 ) for ACPA-positive RA, whereas surprisingly, no SNPs reached this significance for ACPA-negative RA. For ACPA-positive RA, we adjusted for known DRB1 risk alleles and identified additional independent associations with SNPs near HLA-DPB1 (rs3117213; odds ratio 1.42 [95% confidence interval 1.17-1.73], P combined ‫؍‬ 0.0003 for the strongest association).Conclusion. There are distinct genetic patterns of MHC associations in the 2 disease subsets of RA defined according to ACPA status. HLA-DPB1 is an independent risk locus for ACPA-positive RA. We did not identify any associations with SNPs within the MHC for ACPA-negative RA.

Objective. The protective effect of HLA-DRB1 alleles on the development of rheumatoid arthritis (RA) is poorly understood. The aim of this study was to perform a meta-analysis of 4 European populations to investigate which HLA-DRB1 alleles are associated with protection in anti-citrullinated protein antibody (ACPA)-positive RA and ACPA-negative RA.Methods. Data for >2,800 patients and >3,000 control subjects for whom information on HLA-DRB1 typing and ACPA status was available were collected from 4 European countries: Norway, Sweden, The Netherlands, and Spain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the different HLA-DRB1 alleles were analyzed in a combined meta-analysis focused on protective alleles and classifications. The analysis of ACPA-positive RA was stratified for the shared epitope (SE) alleles, to correct for skewing due to this association.Results. In ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA-DRB1*13 alleles (OR 0.54 [95% CI 0.38-0.77]). The protective effect of the allele classifications based on the DERAA and D70 sequences was no longer present after exclusion of DRB1*13 (for D70, OR 0.97

Objective. An interaction effect for developing rheumatoid arthritis (RA) was previously observed between HLA-DRB1 shared epitope (SE) alleles and smoking. We aimed to further investigate this interaction between distinct SE alleles and smoking regarding the risk of developing RA with and without anticitrullinated protein antibodies (ACPAs).Methods. We used data regarding smoking habits and HLA-DRB1 genotypes from 1,319 patients and 943 controls from the Epidemiological Investigation of Rheumatoid Arthritis, in which 972 patients and 488 controls were SE positive. Subsequently, 759 patients and 328 controls were subtyped for specific alleles within the DRB1*04 group. Odds ratios with 95% confidence intervals (95% CIs) were calculated by means of logistic regression. Interaction was evaluated by calculating attributable proportion due to interaction, with 95% CIs. Conclusion.There is a statistically significant interaction between distinct DRB1 SE alleles and smoking in the development of ACPA-positive RA. Interaction occurs with the *04 group as well as the *01/*10 group, demonstrating that regardless of fine specificity, all SE alleles strongly interact with smoking in conferring an increased risk of ACPA-positive RA.

Objective. The effect of non-shared epitope HLA-DRB1 alleles on rheumatoid arthritis (RA) is poorly understood. This study was undertaken to investigate the effects of several HLA-DRB1 alleles, independent of the shared epitope, on the risk of developing anticitrullinated protein antibody (ACPA)-positive or ACPA-negative RA in a large case-control study. Conclusion. Our findings indicate that the DRB1*13 allele plays a dual role in the development of RA, by protecting against ACPA-positive RA but, in combination with DRB1*03, increasing the risk of ACPA-negative RA.