title: Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves' disease.
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 (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.
authors.affiliation: Institute of Biomedical Research, University of Birmingham, Edgbaston, West Midlands, UK.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Brand
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Barrett
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Simmonds
authors.forename: Paul R
authors.initials: PR
authors.lastname: Newby
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McCabe
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Bruce
authors.forename: Boris
authors.initials: B
authors.lastname: Kysela
authors.forename: Jackie D
authors.initials: JD
authors.lastname: Carr-Smith
authors.forename: Thomas
authors.initials: T
authors.lastname: Brix
authors.forename: Penny J
authors.initials: PJ
authors.lastname: Hunt
authors.forename: Wilmar M
authors.initials: WM
authors.lastname: Wiersinga
authors.forename: Laszlo
authors.initials: L
authors.lastname: Hegedüs
authors.forename: John
authors.initials: J
authors.lastname: Connell
authors.forename: John A H
authors.initials: JA
authors.lastname: Wass
authors.forename: Jayne A
authors.initials: JA
authors.lastname: Franklyn
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Weetman
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Heward
authors.forename: Stephen C L
authors.initials: SC
authors.lastname: Gough
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D015870:Gene Expression; D006111:Graves Disease / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D011989:Receptors, Thyrotropin