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

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...

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Vydané v:	Human molecular genetics Ročník 18; číslo 9; s. 1704
Hlavní autori:	Brand, Oliver J, Barrett, Jeffrey C, Simmonds, Matthew J, Newby, Paul R, McCabe, Christopher J, Bruce, Christopher K, Kysela, Boris, Carr-Smith, Jackie D, Brix, Thomas, Hunt, Penny J, Wiersinga, Wilmar M, Hegedüs, Laszlo, Connell, John, Wass, John A H, Franklyn, Jayne A, Weetman, Anthony P, Heward, Joanne M, Gough, Stephen C L
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England 01.05.2009
Predmet:	Case-Control Studies Cohort Studies Gene Expression Graves Disease - genetics Graves Disease - metabolism Haplotypes Humans Introns Linkage Disequilibrium Polymorphism, Single Nucleotide Receptors, Thyrotropin - genetics Receptors, Thyrotropin - metabolism White People - genetics
ISSN:	1460-2083, 1460-2083
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Popis
Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1460-2083 1460-2083
DOI:	10.1093/hmg/ddp087