HLA and CTLA4 polymorphisms may confer a synergistic risk in the susceptibility to Graves' disease

Graves' disease (GD) is an autoimmune disease characterized by hyperthyroidism due to the presence of autoantibodies against thyroid-stimulating hormone receptor, which is measured as thyroid-stimulating hormone-binding inhibitory immunoglobulin (TBII). Most of the GD patients are TBII-positive, but TBII is undetectable in a proportion of GD patients. We previously reported the association of HLA-A 02 and -DPB1 0501 with TBII-positive GD, whereas TBII-negative GD showed association with HLA-A 02 and DPB1 0202. Recently, polymorphisms of cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) gene are reported to be associated with GD. In this study, we investigated 329 (240 TBII-positive and 89 TBII-negative) GD patients and 378 controls for the polymorphisms in HLA-A, -DPB1 and CTLA4 (CT60, rs3087243, A/G) to investigate the contribution of these factors in the susceptibility to GD. A significant association with CTLA4 was found for the TBII-positive GD (G carriers in patients vs controls, 97.1 vs 91.8%; odds ratio (OR)=2.97, 95% confidence interval=1.29-6.87, P=0.008), but the association was weak and not significant for the TBII-negative GD (94.4 vs 91.8%; OR=1.50, 95% confidence interval=0.57-3.98, P=0.41). Stratification analyses suggested a possible synergistic interaction of CTLA4 with HLA-A 02 and -DPB1 0501 in the susceptibility to TBII-positive GD.