Association of the HLA–DRB1 epitope LA67, 74 with rheumatoid arthritis and citrullinated vimentin binding

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 (V¹¹, H¹³, and L⁶⁷) were found to have the highest degree of association with RA susceptibility (P < 10^–11), and D⁷⁰ 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 D⁷⁰. Only 1 allele (DRB1*16:02) contained both LA^{67, 74} and D⁷⁰; 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.