Human Molecular Genetics Advance Access published online on June 27, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm165
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A novel and major association of HLA-C in Graves' disease that eclipses the classical HLA-DRB1 effect
1 Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK 2 Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
* Corresponding author: Stephen C L Gough, Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK. Tel: - (44) 121 415 8819, Fax: - (44) 121 415 8712 Email: - s.c.gough{at}bham.ac.uk
Received April 27, 2007; Revised June 22, 2007; Accepted June 22, 2007
Association of the MHC class II encoded HLA-DRB1-DQA1-DQB1 haplotype with Graves' disease 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 Graves' disease in a white ethnic group of 806 patients with Graves' disease and 487 control subjects from the UK. Of the five loci (HLA-B, -C, -DRB1, - DQA1, -DQB1) HLA-C demonstrated the strongest association (P = 1.20x10-20) 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 = 1.54x10–6) 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 Graves' disease. Class II loci could still have effects in Graves' disease, 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 Graves' disease, a condition classically assumed to be a straightforward HLA-class II-restricted autoantibody response to the TSH receptor.
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