There are distinct genetic patterns of major histocompatibility complex (MHC) associations in the two disease subsets of rheumatoid arthritis (RA), study findings indicate.
“RA can be divided into two major clinical subtypes that are defined by the presence or absence of antibodies to citrullinated protein antigens (ACPA),” explain Bo Ding (Karolinska Institute, Stockholm, Sweden) and co-authors.
They add that it was recently demonstrated that HLA-DRB1 shared epitope alleles in the MHC locus are associated with the risk for ACPA-positive RA but not ACPA-negative disease.
To identify additional variants in the MHC region that independently contribute to risk in the two disease subsets of RA, Ding and team used a multistep strategy to analyze 2221 single nucleotide polymorphisms (SNPs) spanning 10.7 Mb, from 6p22.20 to 6p21.31, across the MHC.
For ACPA-positive RA, the researchers analyzed samples from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) and the North American Rheumatoid Arthritis Consortium studies including a total of 1255 cases and 1719 controls.
For ACPA-negative RA, they used samples from the EIRA study totaling 640 cases and 670 controls.
A total of 299 SNPs reached locus-wide significance for ACPA-positive RA. In contrast, no SNPs reached significance for ACPA-negative RA despite similar statistical power for the two subsets of RA cases in the EIRA study.
“This provides strong evidence of genetically distinct etiologies behind these two forms of RA,” say Ding et al in the journal Arthritis and Rheumatism.
Further analysis of ACPA-positive RA, adjusted for known HLA-DRB1 risk alleles, identified additional independent associations with SNPs near HLA-DPB1. The strongest association was seen for the SNP rs3117213.
This leads the authors to conclude: “HLA-DPB1 is an independent risk locus for ACPA-positive RA.”
They add: “These findings support a model in which the role of MHC-dependent adaptive immunity is restricted to ACPA-positive RA and in which at least two, and possibly more, different class II MHC loci may be involved in the pathogenesis of the ACPA-positive RA.”