Bos Maxime M, Smit Roelof A J, Trompet Stella, van Heemst Diana, Noordam Raymond
Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Department of Cardiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
J Clin Endocrinol Metab. 2017 Jun 1;102(6):1960-1970. doi: 10.1210/jc.2016-2816.
Increasing evidence suggests an association between thyroid-stimulating hormone (TSH), free thyroxine (fT4), and deiodinases with insulin resistance and type 2 diabetes mellitus (T2D).
We examined whether TSH and fT4 levels and deiodinases are causally associated with insulin resistance and T2D, using Mendelian randomization.
We selected 20 genetic variants for TSH level and four for fT4 level (identified in a genome-wide association study (GWAS) meta-analysis of European-ancestry cohorts) as instrumental variables for TSH and fT4 levels, respectively. We used summary data from GWASs on the outcomes T2D [Diabetes, Genetics Replication and Meta-analysis (DIAGRAM), n = 12,171 cases and n = 56,862 control subjects] and glycemic traits in patients without diabetes [Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), n = 46,186 for fasting glucose and insulin and n = 46,368 for hemoglobin A1c]. To examine whether the associations between TSH/fT4 levels and the study outcomes were causal, we combined the effects of the genetic instruments. Furthermore, we examined the associations among 16 variants in DIO1, DIO2, DIO3, and T2D and glycemic traits.
We found no evidence for an association between the combined genetic instrumental variables for TSH and fT4 and the study outcomes. For example, we did not observe a genetically determined association between high TSH level and T2D (odds ratio, 0.91 per standard deviation TSH increase; 95% confidence interval, 0.78 to 1.07). Selected genetic variants in DIO1 (e.g., rs7527713) were associated with measures of insulin resistance.
We found no evidence for a causal association between circulatory levels of TSH and fT4 with insulin resistance and T2D, but we found suggestive evidence that DIO1 affects glucose metabolism.
越来越多的证据表明促甲状腺激素（TSH）、游离甲状腺素（fT4）和脱碘酶与胰岛素抵抗及2型糖尿病（T2D）之间存在关联。
我们使用孟德尔随机化方法研究TSH和fT4水平以及脱碘酶是否与胰岛素抵抗和T2D存在因果关系。
我们分别选择了20个与TSH水平相关的基因变异和4个与fT4水平相关的基因变异（在欧洲血统队列的全基因组关联研究（GWAS）荟萃分析中确定）作为TSH和fT4水平的工具变量。我们使用了GWAS关于T2D [糖尿病、遗传学复制与荟萃分析（DIAGRAM），12171例病例和56862例对照]以及无糖尿病患者血糖特征[葡萄糖和胰岛素相关特征荟萃分析联盟（MAGIC），空腹血糖和胰岛素为46186例，糖化血红蛋白为46368例]的汇总数据。为了研究TSH/fT4水平与研究结果之间的关联是否具有因果性，我们合并了基因工具的效应。此外，我们研究了DIO1、DIO2、DIO3中的16个变异与T2D及血糖特征之间的关联。
我们没有发现TSH和fT4的联合基因工具变量与研究结果之间存在关联的证据。例如，我们没有观察到高TSH水平与T2D之间存在基因决定的关联（优势比，TSH每增加一个标准差为0.91；95%置信区间，0.78至1.07）。DIO1中选定的基因变异（如rs7527713）与胰岛素抵抗指标相关联。
我们没有发现循环中TSH和fT4水平与胰岛素抵抗和T2D之间存在因果关联的证据，但我们发现了提示性证据表明DIO1影响葡萄糖代谢。
