Thyroid Stimulating Hormone Receptor (TSHR) Intron 1 Variants Are Major Risk Factors for Graves' Disease in Three European Caucasian Cohorts

Rafał Płoski,Beata Jurecka-Lubieniecka,Stephen C L Gough,Dorota Kula,Tomasz Bednarczuk,Oliver J Brand,Barbara Jarząb,Paweł Krajewski,Matthew J Simmonds,Muhammad A Karamat,Maria Franaszczyk,Jayne A Franklyn,Amanda Ewart Toland

doi:10.1371/journal.pone.0015512

Abstract

BackgroundThe thyroid stimulating hormone receptor (TSHR) gene is an established susceptibility locus for Graves' disease (GD), with recent studies refining association to two single nucleotide polymorphisms (SNPs), rs179247 and rs12101255, within TSHR intron 1.Methodology and Principal FindingsWe aimed to validate association of rs179247 and rs12101255 in Polish and UK Caucasian GD case-control subjects, determine the mode of inheritance and to see if association correlates with specific GD clinical manifestations. We investigated three case-control populations; 558 GD patients and 520 controls from Warsaw, Poland, 196 GD patients and 198 controls from Gliwice, Poland and 2504 GD patients from the UK National collection and 2784 controls from the 1958 British Birth cohort. Both rs179247 (P = 1.2×10−2–6.2×10−15, OR = 1.38–1.45) and rs12101255 (P = 1.0×10−4–3.68×10−21, OR = 1.47–1.87) exhibited strong association with GD in all three cohorts. Logistic regression suggested association of rs179247 is secondary to rs12101255 in all cohorts. Inheritance modeling suggested a co-dominant mode of inheritance in all cohorts. Genotype-phenotype correlations provided no clear evidence of association with any specific clinical characteristics.ConclusionsWe have validated association of TSHR intron 1 SNPs with GD in three independent European cohorts and have demonstrated that the aetiological variant within the TSHR is likely to be in strong linkage disequilibrium with rs12101255. Fine mapping is now required to determine the exact location of the aetiological DNA variants within the TSHR.

Highlights

The thyroid stimulating hormone receptor (TSHR) is primarily expressed on the thyroid follicular cell surface membrane and via its ligand, TSH, is one of the key regulators of thyroid growth and hormone production
We have validated association of TSHR intron 1 single nucleotide polymorphisms (SNPs) with Graves’ disease (GD) in three independent European cohorts and have demonstrated that the aetiological variant within the TSHR is likely to be in strong linkage disequilibrium with rs12101255
TSHR autoantibodies with either stimulatory (TSAb) or blocking (TBAb) activity are a key feature of autoimmune thyroid disease (AITD), with TSAb having a predominant effect in Graves’ disease (GD) leading to hyperthyroidism [1]

Summary

Introduction

The thyroid stimulating hormone receptor (TSHR) is primarily expressed on the thyroid follicular cell surface membrane and via its ligand, TSH, is one of the key regulators of thyroid growth and hormone production. Original TSHR genetic studies focused on several nonsynonymous single nucleotide polymorphisms (nsSNPs) and despite a number of studies, no replicable GD associations emerged [2,3,4,5,6,7,8]. The Wellcome Trust Case Control Consortium (WTCCC) identified association of a further TSHR nsSNP rs3783941 (Arg248Ser) with GD in a genome wide screen of 15,000 nsSNPs in 900 UK Caucasian GD cases and 1500 controls [12]. Recent detailed association mapping of 98 SNPs across 800Kb of the TSHR region, refined association to within 40Kb of TSHR intron 1 in 768 GD patients and 768 controls of UK Caucasian origin [13]. The thyroid stimulating hormone receptor (TSHR) gene is an established susceptibility locus for Graves’ disease (GD), with recent studies refining association to two single nucleotide polymorphisms (SNPs), rs179247 and rs12101255, within TSHR intron 1

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