Association of the HLA-DRB1 epitope LA(67, 74) with rheumatoid arthritis and citrullinated vimentin binding.
Arthritis Rheum
; 63(12): 3733-9, 2011 Dec.
Article
en En
| MEDLINE
| ID: mdl-22094856
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*1602) 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Péptidos Cíclicos
/
Artritis Reumatoide
/
Vimentina
/
Cadenas HLA-DRB1
/
Epítopos
Tipo de estudio:
Clinical_trials
/
Observational_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Arthritis Rheum
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos