title: Association of the HLA-DRB1 epitope LA(67, 74)  with rheumatoid arthritis and citrullinated vimentin binding.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: ClinImmune Labs and University of Colorado School of Medicine, Aurora, CO 80045, USA. Brian.Freed@ucdenver.edu
authors.forename: Brian M
authors.initials: BM
authors.lastname: Freed
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Schuyler
authors.forename: Michael T
authors.initials: MT
authors.lastname: Aubrey
mesh_terms: D000483:Alleles; D000596:Amino Acids / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism*; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D000939:Epitopes / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007391:International Cooperation; D010456:Peptides, Cyclic / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D014746:Vimentin / Q000378:metabolism*; D044465:White People / Q000235:genetics
chemical_list: D000596:Amino Acids; D000939:Epitopes; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; D014746:Vimentin; C487763:cyclic citrullinated peptide