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Association of the major histocompatibility complex (MHC) class II-encoded  HLA-DRB1-DQA1-DQB1  haplotype with Graves' disease (GD) has been known for several years. Recent evidence from other autoimmune diseases has suggested that the HLA class I encoded HLA-B/-C molecules could be conferring  HLA-DRB1-DQA1-DQB1  independent effects on disease. The aim of this study was to determine the effect of  HLA-B  and  HLA-C  in GD in a white ethnic group of 806 patients with GD and 487 control subjects from the UK. Of the five loci ( HLA-B ,  -C ,  -DRB1 ,  -DQA1 ,  -DQB1 ),  HLA-C  demonstrated the strongest association ( P  = 1.20 × 10 −20 ) with HLA-C*07 predisposing [OR = 1.63, 95% CI (1.23–2.17)] and both HLA-C*03 [OR = 0.54, 95% CI (0.38–0.77)], HLA-C*16 [OR = 0.36, 95% CI (0.21–0.61)] protective. The other loci were then tested for  HLA-C -independent associations.  HLA-B  was found to be associated independently of  HLA-C  ( P  = 1.54 × 10 −6 ) with the other three loci,  HLA-DRB1 ,  HLA-DQB1  and  HLA-DQA1 , also improving the model but with less confidence ( P  &gt; 10 −5 ). This study has for the first time provided evidence of a primary association of  HLA-C , and to a lesser extent  HLA-B , with GD. Class II loci could still have effects on GD, but they appear smaller than the  HLA-C  association. A full investigation of the MHC region, including all class I and II loci is now required. Our results point to a primary role for class I-mediated responses in GD, a condition classically assumed to be a straightforward HLA-class II-restricted autoantibody response to the thyroid stimulating hormone receptor.

A novel and major association of HLA-C in Graves' disease that eclipses the classical HLA-DRB1 effect