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

2007; Oxford University Press; Volume: 16; Issue: 18 Linguagem: Inglês

10.1093/hmg/ddm165

1460-2083

Matthew J. Simmonds, Joanna M. M. Howson, J. M. Heward, Jackie Carr‐Smith, Jayne A. Franklyn, John A. Todd, Stephen Gough,

Immune Cell Function and Interaction

Abstract 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 > 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.