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Human Molecular Genetics Advance Access published online on February 25, 2009
Human Molecular Genetics, 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 (GD)

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 Brix3, Penny J. Hunt1, Wilmar M. Wiersinga4, Laszlo Hegedus3, John Connell5, John A. H. Wass6, 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, Birmingham, West Midlands, B15 2TT, UK 2 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK 3 Department of Endocrinology and Metabolism, Odense University Hospital, Denmark 4 Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, The Netherlands 5 University of Glasgow, Glasgow, UK 6 University of Oxford, Department of Endocrinology, Churchill Hospital, Oxford, UK 7 Medical School, University of Sheffield, Sheffield, UK

* Correspondence Prof Stephen CL Gough, School of Clinical of Experimental Medicine, College of Medical and Dental Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, UK Tel: (44) 121 4158819 Fax: (44) 121 4158712 Email: s.c.gough{at}bham.ac.uk

Received December 23, 2008; Revised February 20, 2009; 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 (TSH), 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 800Kb 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=8.90x10–8, OR=1.53, 95% CI=1.32 - 1.78) and rs12101255 ({chi}2=30.91, P=1.95x10–7, 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=7.8x10–4). 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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