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

作者：Freed Brian M^*; Schuyler Ronald P; Aubrey Michael T

来源：Arthritis and Rheumatism, 2011, 63(12): 3733-3739.

DOI：10.1002/art.30636

Objective Although rheumatoid arthritis (RA) has long been associated with an HLADRB1 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 x 10(-11)). Of > 2 million epitopes examined, LA67, 74 exhibited the highest correlation with RA susceptibility (P = 2 x 10(-20); odds ratio 4.07 [ 95% confidence interval 3.07-5.39]). HLA alleles containing the LA67, 74 epitope exhibited significantly greater binding to citrullinated vimentin65-77 than did alleles containing D70. Only 1 allele (DRB1* 16: 02) contained both LA67, 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.

• 出版日期2011-12