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Association of the TSHR gene with Graves' disease: the first disease specific locus

2005; Springer Nature; Volume: 13; Issue: 11 Linguagem: Inglês

10.1038/sj.ejhg.5201485

1476-5438

Bryan Dechairo, Delilah Zabaneh, J Collins, Stephan Brand, Gary Dawson, Angie P Green, Ian Mackay, Jayne A. Franklyn, John Connell, John Wass, Wilmar M. Wiersinga, László Hegedűs, Thomas Heiberg Brix, Bruce G. Robinson, Penny J. Hunt, Anthony P. Weetman, Alisoun H. Carey, Stephen Gough,

Pancreatic function and diabetes

The development of autoimmune thyroid disease (AITD) is associated with autoantibodies directed against the thyroid stimulating hormone receptor (TSHR). Previous studies have failed to demonstrate a consistent association between the TSHR and AITD, or any of its sub-phenotypes. In the present study, we analysed the linkage disequilibrium (LD) structure encompassing the TSHR, to identify LD ‘blocks’ and SNPs, which capture the majority of intra-block haplotype diversity. The haplotype tagging SNPs, plus all common SNPs reported in previous studies were genotyped in 1059 AITD Caucasian cases and 971 Caucasian controls. A haplotype, across two LD blocks, showed association (P<1 × 10−6, OR 1.7) with Graves’ disease (GD) but not autoimmune hypothyroidism (AIH). We replicated these findings by genotyping the most associated GD SNP, rs2268458, in a separate UK Caucasian cohort of 1366 AITD cases and 1061 controls (GD, P=2 × 10−6, OR 1.3; AIH, P=NS). These results in two independent Caucasian data sets suggest that the TSHR is the first replicated GD-specific locus meriting further fine mapping and functional analysis to identify the aetiological variants.