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

Oliver J. Brand, Jaffrey C. Barrett, Mathew J. Simmonds, Paul R. Newby, Christpher J. McCabe, Christpher K. Bruce, Boris Kysela, Jackie D. Carr-Smith, Thomas Brix, Penny J. Hunt, Wilmar M. Wiersinga, Laszio Hegedüs, John Connell, John A.H. Wass, Jayne A. Franklyn, Anthony P. Weetman, Joanne M. Heward, Stephen C.L. Gough

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    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 (?2 = 32.45, P = 8.90 × 10-8, OR = 1.53, 95% CI = 1.32-1.78) and rs12101255 (?2 = 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. © The Author 2009. Published by Oxford University Press. All rights reserved.
    Original languageUndefined/Unknown
    Pages (from-to)1704-1713
    Number of pages10
    JournalHuman Molecular Genetics
    Issue number9
    Publication statusPublished - 2009


    • messenger RNA
    • thyrotropin receptor
    • article
    • cohort analysis
    • controlled study
    • gene expression
    • gene function
    • gene linkage disequilibrium
    • gene locus
    • gene replication
    • genetic association
    • genetic identification
    • genetic susceptibility
    • genetic variability
    • genotype
    • Graves disease
    • haplotype
    • human
    • intron
    • major clinical study
    • phenotype
    • priority journal
    • promoter region
    • single nucleotide polymorphism
    • Case-Control Studies
    • Cohort Studies
    • European Continental Ancestry Group
    • Gene Expression
    • Graves Disease
    • Haplotypes
    • Humans
    • Introns
    • Linkage Disequilibrium
    • Polymorphism, Single Nucleotide
    • Receptors, Thyrotropin

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