Association of the HLA-DRB1 epitope LA(67, 74) with rheumatoid arthritis and citrullinated vimentin binding

Arthritis Rheum. 2011 Dec;63(12):3733-9. doi: 10.1002/art.30636.

Abstract

Objective: Although rheumatoid arthritis (RA) has long been associated with an HLA-DRB1 shared epitope, a systematic search for other epitopes has never been conducted. In addition, the relationship between these epitopes and the binding of citrullinated autoantigens has not been investigated. We developed a program that can analyze HLA data for all possible epitopes of up to 5 amino acids and used this program to assess the shared epitope hypothesis in RA.

Methods: We analyzed high-resolution data from the International Histocompatibility Working Group, which included a group of 488 patients with RA and a group of 448 racially and ethnically balanced control subjects, for all combinations of up to 5 amino acids among polymorphic HLA-DRB1 positions 8-93. Statistical significance was determined by chi-square and Fisher's exact tests, with a false discovery rate correction.

Results: Three residues (V(11), H(13), and L(67)) were found to have the highest degree of association with RA susceptibility (P < 10(-11)), and D(70) was found to correlate best with RA resistance (P = 2 × 10(-11)). Of >2 million epitopes examined, LA(67, 74) exhibited the highest correlation with RA susceptibility (P = 2 × 10(-20); odds ratio 4.07 [95% confidence interval 3.07-5.39]). HLA alleles containing the LA(67, 74) epitope exhibited significantly greater binding to citrullinated vimentin(65-77) than did alleles containing D(70). Only 1 allele (DRB1*16:02) contained both LA(67, 74) and D(70); it bound citrullinated vimentin weakly and was not associated with RA.

Conclusion: The findings of these studies confirm the importance of HLA-DRB1 amino acids in pocket 4 for the binding of citrullinated autoantigens and susceptibility to RA.

Publication types

  • Multicenter Study

MeSH terms

  • Alleles
  • Amino Acids / metabolism
  • Arthritis, Rheumatoid / ethnology
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / metabolism*
  • Asians / genetics
  • Blacks / genetics
  • Case-Control Studies
  • Epitopes / genetics*
  • Genetic Predisposition to Disease / genetics
  • HLA-DRB1 Chains / chemistry
  • HLA-DRB1 Chains / genetics*
  • Humans
  • International Cooperation
  • Peptides, Cyclic / metabolism*
  • Protein Binding / genetics
  • Vimentin / metabolism*
  • Whites / genetics

Substances

  • Amino Acids
  • Epitopes
  • HLA-DRB1 Chains
  • Peptides, Cyclic
  • Vimentin
  • cyclic citrullinated peptide