HLA-DRB1 alleles and shared amino acid sequences in disease susceptibility and severity in patients from eastern France with rheumatoid arthritis.

Objective. To examine the effects of HLA-DRBI alleles and amino acid sequences that carry the shared epitope (SE) upon rheumatoid arthritis (RA) susceptibility and disease severity in patients from Eastern France. Methods. HLA-DRBI alleles were determined in 120 patients and 104 healthy controls by polymerase chain reaction/sequence specific oligonucleotide probes. Subtyping of DRB1 * 01 and * 04 were performed using sequence specific primers. Patients were retrospectively evaluated for disease duration, age at disease onset, presence of rheumatoid factors, subcutaneous nodules, vasculitis and other extraarticular diseases, for the need for arthroplasty and immunosuppressive/immunoregulatory agents, and for radiographic damage. Results. The prevalence of HLA-DRB1 * 04 was significantly higher in patients (46.6%) than in controls (17.3%) (p corr = 0.000003). HLA-DRB1 * 0101 and * 0401 were the most prominently associated subtypes in patients with RA (33.3%, p = 0.011, and 28.3%, p corr = 0.00008, respectively). A significant fraction of patients (72.5%) expressed one or 2 copies of the SE (p < 0.0000001; OR 4.77, CI 2.61-8.78). The presence of double SE was associated with a higher risk of developing RA (OR 4.83, CI 1.91-12.71; p = 0.0001). No significant differences in the clinical records among patients expressing no RA linked alleles, one and 2 copies of the SE, were observed. However, analyzing the specific effect of each amino acid sequence, we observed a significant association of the QKRAA motif with vasculitis (p = 0.03) and history of joint replacement surgery (p = 0.05), suggesting a role for lysine in position 71 of the shared sequence. Conclusion. These findings differ from those of previous HLA-DRB I allele studies in patients with RA from other regions of France. Thus,the heterogeneity in both the expression of DRB 1 alleles and the association of these alleles with disease severity could be relevant within a country such as France.