Systematic approach demonstrates enrichment of multiple interactions between non-<i>HLA</i> risk variants and <i>HLA-DRB1</i> risk alleles in rheumatoid arthritis.

Abstract

In anti-citrullinated protein antibody positive rheumatoid arthritis (ACPA-positive RA), a particular subset of <i>HLA-DRB1</i> alleles, called shared epitope (SE) alleles, is a highly influential genetic risk factor. Here, we investigated whether non-<i>HLA</i> single nucleotide polymorphisms (SNP), conferring low disease risk on their own, interact with SE alleles more frequently than expected by chance and if such genetic interactions influence the <i>HLA-DRB1</i> SE effect concerning risk to ACPA-positive RA. We computed the attributable proportion (AP) due to additive interaction at genome-wide level for two independent ACPA-positive RA cohorts: the Swedish epidemiological investigation of rheumatoid arthritis (EIRA) and the North American rheumatoid arthritis consortium (NARAC). Then, we tested for differences in the AP p value distributions observed for two groups of SNPs, non-associated and associated with disease. We also evaluated whether the SNPs in interaction with <i>HLA-DRB1</i> were cis-eQTLs in the SE alleles context in peripheral blood mononuclear cells from patients with ACPA-positive RA (SE-eQTLs). We found a strong enrichment of significant interactions (AP p<0.05) between the <i>HLA-DRB1</i> SE alleles and the group of SNPs associated with ACPA-positive RA in both cohorts (Kolmogorov-Smirnov test D=0.35 for EIRA and D=0.25 for NARAC, p<2.2e-16 for both). Interestingly, 564 out of 1492 SNPs in consistent interaction for both cohorts were significant SE-eQTLs. Finally, we observed that the effect size of <i>HLA-DRB1</i> SE alleles for disease decreases from 5.2 to 2.5 after removal of the risk alleles of the two top interacting SNPs (rs2476601 and rs10739581). Our data demonstrate that there are massive genetic interactions between the <i>HLA-DRB1</i> SE alleles and non-<i>HLA</i> genetic variants in ACPA-positive RA.