The effect of HLA‐DR genes on susceptibility to and severity of ankylosing spondylitis

Objective To analyze the effect of HLA‐DR genes on susceptibility to and severity of ankylosing spondylitis (AS). Methods Three hundred sixty‐three white British AS patients were studied; 149 were carefully assessed for a range of clinical manifestations, and disease severity was assessed using a structured questionnaire. Limited HLA class I typing and complete HLA‐DR typing were performed using DNA‐based methods. HLA data from 13,634 healthy white British bone marrow donors were used for comparison. Results A significant association between DR1 and AS was found, independent of HLA‐B27 (overall odds ratio [OR] 1.4, 95% confidence interval [95% CI] 1.1‐1.8, P = 0.02; relative risk [RR] 2.7, 95% CI 1.5‐4.8, P = 6 × 10‐4 among homozygotes; RR 2.1, 95% CI 1.5‐2.8, P = 5 × 10‐6 among heterozygotes). A large but weakly significant association between DR8 and AS was noted, particularly among DR8 homozygotes (RR 6.8, 95% CI 1.6‐29.2, P = 0.01 among homozygotes; RR 1.6, 95% CI 1.0‐2.7, P = 0.07 among heterozygotes). A negative association with DR12 (OR 0.22, 95% CI 0.09‐0.5, P = 0.001) was noted. HLA‐DR7 was associated with younger age at onset of disease (mean age at onset 18 years for DR7‐positive patients and 23 years for DR7‐negative patients; Z score 3.21, P = 0.001). No other HLA class I or class II associations with disease severity or with different clinical manifestations of AS were found. Conclusion The results of this study suggest that HLA‐DR genes may have a weak effect on susceptibility to AS independent of HLA‐B27, but do not support suggestions that they affect disease severity or different clinical manifestations.