Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis

Am J Hum Genet. 2016 Aug 4;99(2):366-74. doi: 10.1016/j.ajhg.2016.06.019.

Abstract

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. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.

Publication types

  • Validation Study

MeSH terms

  • Arthritis, Rheumatoid / genetics*
  • Asians / genetics*
  • Autoantibodies
  • Citrulline
  • Ethnicity / genetics
  • Europe / ethnology
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • HLA-D Antigens / genetics*
  • HLA-DRB1 Chains / genetics
  • Humans
  • Japan / ethnology
  • Linkage Disequilibrium / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Whites / genetics

Substances

  • Autoantibodies
  • HLA-D Antigens
  • HLA-DRB1 Chains
  • Citrulline