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Human Molecular Genetics Advance Access originally published online on February 25, 2009
Human Molecular Genetics 2009 18(9):1704-1713; doi:10.1093/hmg/ddp087
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Oliver J. Brand1, Jeffrey C. Barrett2, Matthew J. Simmonds1, Paul R. Newby1, Christopher J. McCabe1, Christopher K. Bruce1, Boris Kysela1, Jackie D. Carr-Smith1, Thomas Brix4, Penny J. Hunt1, Wilmar M. Wiersinga5, Laszlo Hegedüs4, John Connell6, John A.H. Wass3, Jayne A. Franklyn1, Anthony P. Weetman7, Joanne M. Heward1 and Stephen C.L. Gough1,*

1 School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, West Midlands B15 2TT, UK 2 Wellcome Trust Centre for Human Genetics and 3 Department of Endocrinology, Churchill Hospital, University of Oxford, Oxford, UK 4 Department of Endocrinology and Metabolism, Odense University Hospital, Denmark 5 Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, The Netherlands 6 University of Glasgow, Glasgow, UK and 7 Medical School, University of Sheffield, Sheffield, UK

* To whom correspondence should be addressed. Tel: +44 1214158819; Fax: +44 1214158712; Email: s.c.gough{at}bham.ac.uk

Received December 23, 2008; Accepted February 20, 2009

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 ({chi}2 = 32.45, P = 8.90 x 10–8, OR = 1.53, 95% CI = 1.32–1.78) and rs12101255 ({chi}2 = 30.91, P = 1.95 x 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 x 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.


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