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

Simmonds, M. J. and Howson, J. M. M. and Heward, J. M. and Carr-Smith, J. and Franklyn, J. A. and Todd, J. A. and Gough, S. C. L. (2007) A novel and major association of HLA-C in Graves' disease that eclipses the classical HLA-DRB1 effect. Human Molecular Genetics, 16 (18). pp. 2149-2153. ISSN 0964-6906

Full content URL: http://dx.doi.org/10.1093/hmg/ddm165

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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. © The Author 2007. Published by Oxford University Press. All rights reserved.

Keywords:autoantibody, HLA B antigen, HLA C antigen, HLA DQA1 antigen, HLA DQB1 antigen, HLA DR antigen, major histocompatibility antigen class 1, major histocompatibility antigen class 2, thyrotropin receptor, allele, antibody response, article, Caucasian, controlled study, female, gene frequency, gene linkage disequilibrium, gene locus, genetic association, genetic predisposition, genetic variability, Graves disease, haplotype map, human, immunopathogenesis, major clinical study, male, priority journal, United Kingdom, Autoantibodies, European Continental Ancestry Group, HLA-B Antigens, HLA-C Antigens, HLA-DR Antigens, Humans, Quantitative Trait Loci, Receptors, Thyrotropin
Subjects:C Biological Sciences > C420 Human Genetics
Divisions:College of Science > School of Life Sciences
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ID Code:22625
Deposited On:30 Mar 2016 08:51

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