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

• Published in: Human molecular genetics Vol. 16; no. 18; pp. 2149 - 2153
• Main Authors: Simmonds, Matthew J., Howson, Joanna M.M., Heward, Joanne M., Carr-Smith, Jackie, Franklyn, Jayne A., Todd, John A., Gough, Stephen C.L.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.09.2007; Oxford Publishing Limited (England)
• Subjects: Autoantibodies - genetics; Autoantibodies - immunology; Biological and medical sciences; Endocrinopathies; European Continental Ancestry Group; Female; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Graves Disease - genetics; Graves Disease - immunology; HLA-B Antigens - genetics; HLA-B Antigens - immunology; HLA-C Antigens - genetics; HLA-C Antigens - immunology; HLA-DR Antigens - genetics; HLA-DR Antigens - immunology; HLA-DRB1 Chains; Humans; Male; Medical sciences; Molecular and cellular biology; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Quantitative Trait Loci - genetics; Quantitative Trait Loci - immunology; Receptors, Thyrotropin - genetics; Receptors, Thyrotropin - immunology; Thyroid. Thyroid axis (diseases); Endocrinopathy; Immunopathology; Association; Hyperthyroidism; Thyroid diseases; Graves disease; Genetics; Autoimmune disease
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddm165

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.