William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Centre for Genomic Health, Life Sciences, Queen Mary University of London, London, UK.
J Clin Endocrinol Metab. 2020 Aug 1;105(8):2634-41. doi: 10.1210/clinem/dgaa239.
Observational studies suggest that variations in normal range thyroid function are associated with cardiovascular diseases. However, it remains to be determined whether these associations are causal or not.
To test whether genetically determined variation in normal range thyroid function is causally associated with the risk of stroke and coronary artery disease (CAD) and investigate via which pathways these relations may be mediated.
DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization analyses for stroke and CAD using genetic instruments associated with normal range thyrotropin (TSH) and free thyroxine levels or Hashimoto's thyroiditis and Graves' disease. The potential mediating role of known stroke and CAD risk factors was examined. Publicly available summary statistics data were used.
Stroke or CAD risk per genetically predicted increase in TSH or FT4 levels.
A 1 standard deviation increase in TSH was associated with a 5% decrease in the risk of stroke (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; P = 0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation. MR analyses did not show a causal association between normal range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto's thyroiditis and a 7% increased risk of CAD (OR, 1.07; 95% CI, 1.01-1.13; P = 0.026), which was mainly mediated via body mass index.
These results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke, and CAD. We identify variation in normal range thyroid function and Hashimoto's thyroiditis as risk factors for stroke and CAD, respectively.
观察性研究表明，甲状腺功能正常范围内的变化与心血管疾病有关。然而，这些关联是否具有因果关系仍有待确定。
检验甲状腺功能正常范围内的遗传决定变异是否与中风和冠心病（CAD）的风险有关，并通过哪些途径来研究这些关联。
设计、地点和参与者：使用与促甲状腺激素（TSH）和游离甲状腺素水平正常范围内的遗传工具，或桥本甲状腺炎和格雷夫斯病相关的遗传工具，进行中风和 CAD 的孟德尔随机分析。研究了已知的中风和 CAD 风险因素的潜在中介作用。使用了公开的汇总统计数据。
每个 TSH 遗传预测值增加所导致的中风或 CAD 风险。
TSH 升高 1 个标准差与中风风险降低 5%相关（比值比[OR]，0.95；95%置信区间[CI]，0.91-0.99；P=0.008）。多变量 MR 分析表明，这种效应主要通过心房颤动来介导。MR 分析未显示甲状腺功能正常范围内的甲状腺功能与 CAD 之间存在因果关系。二级分析表明，桥本甲状腺炎与 CAD 风险增加 7%之间存在因果关系（OR，1.07；95%CI，1.01-1.13；P=0.026），这主要通过体重指数来介导。
这些结果为甲状腺功能、中风和 CAD 之间的因果关系和中介途径提供了重要的新见解。我们确定了甲状腺功能正常范围内的变异和桥本甲状腺炎分别是中风和 CAD 的风险因素。
