Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations

Hum Mol Genet. 2014 Dec 20;23(25):6916-26. doi: 10.1093/hmg/ddu387. Epub 2014 Jul 28.

Abstract

Previous studies have emphasized ethnically heterogeneous human leukocyte antigen (HLA) classical allele associations to rheumatoid arthritis (RA) risk. We fine-mapped RA risk alleles within the major histocompatibility complex (MHC) in 2782 seropositive RA cases and 4315 controls of Asian descent. We applied imputation to determine genotypes for eight class I and II HLA genes to Asian populations for the first time using a newly constructed pan-Asian reference panel. First, we empirically measured high imputation accuracy in Asian samples. Then we observed the most significant association in HLA-DRβ1 at amino acid position 13, located outside the classical shared epitope (Pomnibus = 6.9 × 10(-135)). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His > Phe > Arg > Tyr ≅ Gly > Ser)--but the observed effects in Asians are generally smaller. Applying stepwise conditional analysis, we identified additional independent associations at positions 57 (conditional Pomnibus = 2.2 × 10(-33)) and 74 (conditional Pomnibus = 1.1 × 10(-8)). Outside of HLA-DRβ1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8 × 10(-6)) and HLA-DPβ1 (Phe9, conditional P = 3.0 × 10(-5)) concordant with European populations. Our trans-ethnic HLA fine-mapping study reveals that (i) a common set of amino acid residues confer shared effects in European and Asian populations and (ii) these same effects can explain ethnically heterogeneous classical allelic associations (e.g. HLA-DRB1*09:01) due to allele frequency differences between populations. Our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Amino Acids / genetics
  • Amino Acids / immunology
  • Arthritis, Rheumatoid / ethnology*
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology
  • Asian Continental Ancestry Group
  • Autoantibodies / biosynthesis
  • Chromosome Mapping
  • Citrulline / immunology
  • Epitopes / chemistry
  • Epitopes / immunology
  • European Continental Ancestry Group
  • Gene Expression
  • Gene Frequency
  • HLA-B Antigens / genetics*
  • HLA-B Antigens / immunology
  • HLA-DP beta-Chains / genetics*
  • HLA-DP beta-Chains / immunology
  • HLA-DRB1 Chains / genetics*
  • HLA-DRB1 Chains / immunology
  • Humans
  • Polymorphism, Genetic*
  • Risk

Substances

  • Amino Acids
  • Autoantibodies
  • Epitopes
  • HLA-B Antigens
  • HLA-DP beta-Chains
  • HLA-DPB1 antigen
  • HLA-DRB1 Chains
  • Citrulline