Dosage Contribution of a Non-Classical HLA Gene, HLA-Doa, to the Risk of Rheumatoid Arthritis

Abstract

Background/Purpose: Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging.

Methods: We conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA), an autoimmune disease with chronic destruction of synovial joints in Japanese (6,244 RA cases and 23,731 controls). We applied the HLA imputation method using the reference panel of the Japanese population (n = 908). We further conducted a multi-ethnic validation study by assessing the MHC fine-mapping analyses of RA in east Asians and Europeans (n = 7,097 and 23,149, respectively).

Results: Our study identified a risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated-protein-autoantibody (ACPA)-positive RA risk (rs378352, odds ratio [OR] = 1.20, P = 1.4×10-9), independently from the risk classical HLA genes (HLA-DRB1, HLA-DPB1, and HLA-B). The HLA-DOA risk variant demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression levels, demonstrating its dosage expression effect on RA risk. Independent risk of the HLA-DOA variant was further validated in east Asians (OR = 1.15, P = 0.0040) and Europeans (OR = 1.06, P = 0.031). Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns between HLA-DOA and HLA-DRB1, which explains the observed HLA-DOA variant risk heterogeneity among ethnicities; which was most evident in Japanese but not in Europeans.

Conclusion: Whilst the previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility of the diseases, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to understanding of HLA immunology in human diseases, and suggests the value of incorporating additional ancestry in MHC fine-mapping.