Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease

Brand, O. J. et al. (2009) Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease. Human Molecular Genetics, 18(9), pp. 1704-1713. (doi:10.1093/hmg/ddp087)

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Publisher's URL: http://dx.doi.org/10.1093/hmg/ddp087

Abstract

Graves’ disease (GD) is a common autoimmune disease (AID) that shares many of its susceptibility loci with other AIDs. The thyroid stimulating hormone receptor (TSHR) represents the primary autoantigen in GD, in which autoantibodies bind to the receptor and mimic its ligand, thyroid stimulating hormone, causing the characteristic clinical phenotype. Although early studies investigating the TSHR and GD proved inconclusive, more recently we provided convincing evidence for association of the TSHR region with disease. In the current study, we investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800 kb region of the TSHR to refine association in a cohort of 768 GD subjects and 768 matched controls. In total, 28 SNPs revealed association with GD (P < 0.05), with strongest SNP associations at rs179247 (χ2 = 32.45, P = 8.90 × 10−8, OR = 1.53, 95% CI = 1.32–1.78) and rs12101255 (χ2 = 30.91, P = 1.95 × 10−7, OR = 1.55, 95% CI = 1.33–1.81), both located in intron 1 of the TSHR. Association of the most associated SNP, rs179247, was replicated in 303 GD families (P = 7.8 × 10−4). In addition, we provide preliminary evidence that the disease-associated genotypes of rs179247 (AA) and rs12101255 (TT) show reduced mRNA expression ratios of flTSHR relative to two alternate TSHR mRNA splice variants.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Connell, Professor John
Authors: Brand, O. J., Barrett, J. C., Simmonds, M. J., Newby, P. R., McCabe, C. J., Bruce, C. K., Kysela, B., Carr-Smith, J. D., Brix, T., Hunt, P. J., Wiersinga, W. M., Hegedus, L., Connell, J., Wass, J. A.H., Franklyn, J. A., Weetman, A. P., Heward, J. M., and Gough, S. C.L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN:0964-6906
ISSN (Online):1460-2083
Published Online:25 February 2009
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
392521Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874/71954Institute of Cardiovascular and Medical Sciences
392522Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874/92665Institute of Cardiovascular and Medical Sciences