Department of Medical Biology, University of Split, School of Medicine, Split, 21000 Croatia.
J Clin Endocrinol Metab. 2023 Nov 17;108(12):3190-3200. doi: 10.1210/clinem/dgad371.
Thyroid function has been associated with metabolic syndrome (MetS) in a number of observational studies but the direction of effects and the exact causal mechanism of this relationship is still unknown.
To examine genetically predicted effects of thyroid function on MetS risk and its components, and vice versa, using large-scale summary genetic association data.
We performed a two-sample bidirectional Mendelian randomization (MR) study using summary statistics from the most comprehensive genome-wide association studies (GWAS) of thyroid-stimulating hormone (TSH, n = 119 715), free thyroxine (fT4, n = 49 269), MetS (n = 291 107), and components of MetS: waist circumference (n = 462 166), fasting blood glucose (n = 281 416), hypertension (n = 463 010), triglycerides (TG, n = 441 016) and high-density lipoprotein cholesterol (HDL-C, n = 403 943). We chose the multiplicative random effects inverse variance weighted (IVW) method as the main analysis. Sensitivity analysis included weighted median and mode analysis, as well as MR-Egger and Causal Analysis Using Summary Effect estimates (CAUSE).
Our results suggest that higher fT4 levels lower the risk of developing MetS (OR = 0.96, P = .037). Genetically predicted fT4 was also positively associated with HDL-C (β = 0.02, P = .008), while genetically predicted TSH was positively associated with TG (β = 0.01, P = .044). These effects were consistent across different MR analyses and confirmed with the CAUSE analysis. In the reverse direction MR analysis, genetically predicted HDL-C was negatively associated with TSH (β = -0.03, P = .046) in the main IVW analysis.
Our study suggests that variations in normal-range thyroid function are causally associated with the diagnosis of MetS and with lipid profile, while in the reverse direction, HDL-C has a plausible causal effect on reference-range TSH levels.
在许多观察性研究中，甲状腺功能与代谢综合征（MetS）有关，但这种关系的影响方向和确切的因果机制尚不清楚。
利用大规模汇总遗传关联数据，研究甲状腺功能对 MetS 风险及其成分的遗传预测作用，反之亦然。
我们使用促甲状腺激素（TSH，n = 119715）、游离甲状腺素（fT4，n = 49269）、MetS（n = 291107）以及 MetS 成分（腰围，n = 462166）、空腹血糖（n = 281416）、高血压（n = 463010）、甘油三酯（n = 441016）和高密度脂蛋白胆固醇（HDL-C，n = 403943）的最全面全基因组关联研究的汇总统计数据，进行了两样本双向孟德尔随机化（MR）研究。我们选择了乘法随机效应逆方差加权（IVW）方法作为主要分析方法。敏感性分析包括加权中位数和模式分析，以及 MR-Egger 和使用汇总效应估计的因果分析（CAUSE）。
我们的研究结果表明，较高的 fT4 水平降低了患 MetS 的风险（OR = 0.96，P =.037）。遗传预测的 fT4 与 HDL-C 呈正相关（β = 0.02，P =.008），而遗传预测的 TSH 与 TG 呈正相关（β = 0.01，P =.044）。这些影响在不同的 MR 分析中是一致的，并通过 CAUSE 分析得到了证实。在反向 MR 分析中，在主要 IVW 分析中，遗传预测的 HDL-C 与 TSH 呈负相关（β = -0.03，P =.046）。
本研究表明，正常范围内甲状腺功能的变化与 MetS 的诊断以及血脂谱有关，而在相反的方向上，HDL-C 对参考范围内 TSH 水平有合理的因果作用。
