Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands.
Eur J Endocrinol. 2011 May;164(5):781-8. doi: 10.1530/EJE-10-1130. Epub 2011 Mar 2.
Minor variation in serum thyroid hormone (TH) levels can have important effects on various clinical endpoints. Although 45-65% of the inter-individual variation in serum TH levels is due to genetic factors, the causative genes are not well established. We therefore studied the effects of genetic variation in 68 TH pathway genes on serum TSH and free thyroxine (FT(4)) levels.
Sixty-eight genes (1512 polymorphisms) were studied in relation to serum TSH and FT(4) levels in 1121 Caucasian subjects. Promising hits (P<0.01) were studied in three independent Caucasian populations (2656 subjects) for confirmation. A meta-analysis of all four studies was performed.
For TSH, eight PDE8B polymorphisms (P=4×10(-17)) remained significant in the meta-analysis. For FT(4), two DIO1 (P=8×10(-12)) and one FOXE1 (P=0.0003) polymorphisms remained significant in the meta-analysis. Suggestive associations were detected for one FOXE1 (P=0.0028) and three THRB (P=0.0045) polymorphisms with TSH, and one SLC16A10 polymorphism (P=0.0110) with FT(4), but failed to reach the significant multiple-testing corrected P value (P<0.0022 and P<0.0033 respectively).
Using a large-scale association analysis, we replicated previously reported associations with genetic variation in PDE8B, THRB, and DIO1. We demonstrate effects of genetic variation in FOXE1 on serum FT(4) levels, and borderline significant effects on serum TSH levels. A suggestive association of genetic variation in SLC16A10 with serum FT(4) levels was found. These data provide insight into the molecular basis of inter-individual variation in TH serum levels.
血清甲状腺激素（TH）水平的微小变化可能对各种临床终点产生重要影响。尽管血清 TH 水平的个体间差异有 45-65%归因于遗传因素，但导致这种差异的基因尚未得到很好的确立。因此，我们研究了 68 个 TH 通路基因的遗传变异对血清 TSH 和游离甲状腺素（FT（4））水平的影响。
在 1121 名白种人受试者中，我们研究了 68 个基因（1512 个多态性）与血清 TSH 和 FT（4）水平的关系。对有希望的（P<0.01）结果在三个独立的白种人群体（2656 名受试者）中进行了研究，以确认其结果。对所有四项研究进行了荟萃分析。
对于 TSH，8 个 PDE8B 多态性（P=4×10(-17)）在荟萃分析中仍然显著。对于 FT（4），2 个 DIO1（P=8×10(-12)）和 1 个 FOXE1 （P=0.0003）多态性在荟萃分析中仍然显著。在 TSH 方面，FOXE1（P=0.0028）和 THRB（P=0.0045）的三个多态性以及 SLC16A10 多态性（P=0.0110）与 FT（4）呈显著相关，但未达到显著的多重校正 P 值（P<0.0022 和 P<0.0033 分别）。
通过大规模的关联分析，我们复制了先前报道的与 PDE8B、THRB 和 DIO1 遗传变异相关的结果。我们证明了 FOXE1 遗传变异对血清 FT（4）水平的影响，并发现其对血清 TSH 水平有边缘显著的影响。还发现 SLC16A10 遗传变异与血清 FT（4）水平之间存在提示性关联。这些数据为 TH 血清水平个体间差异的分子基础提供了深入的了解。
