Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
Department of Epidemiology and Biostatistics, Xuzhou Medical University, Xuzhou 221004, China.
Endocrinology. 2021 May 1;162(5). doi: 10.1210/endocr/bqab037.
The association between thyroid function and dyslipidemia has been well documented in observational studies. However, observational studies are prone to confounding, making it difficult to conduct causal inference. We performed a 2-sample bidirectional Mendelian randomization (MR) using summary statistics from large-scale genome-wide association studies of thyroid stimulating hormone (TSH), free T4 (FT4), and blood lipids. We chose the inverse variance-weighted (IVW) method for the main analysis, and consolidated results through various sensitivity analyses involving 6 different MR methods under different model specifications. We further conducted genetic correlation analysis and colocalization analysis to deeply reflect the causality. The IVW method showed per 1 SD increase in normal TSH was significantly associated with a 0.048 SD increase in total cholesterol (TC; P < 0.001) and a 0.032 SD increase in low-density lipoprotein cholesterol (LDL; P = 0.021). A 1 SD increase in normal FT4 was significantly associated with a 0.056 SD decrease in TC (P = 0.014) and a 0.072 SD decrease in LDL (P = 0.009). Neither TSH nor FT4 showed causal associations with high-density lipoprotein cholesterol and triglycerides. No significant causal effect of blood lipids on normal TSH or FT4 can be detected. All results were largely consistent when using several alternative MR methods, and were reconfirmed by both genetic correlation analysis and colocalization analysis. Our study suggested that, even within reference range, higher TSH or lower FT4 are causally associated with increased TC and LDL, whereas no reverse causal association can be found.
甲状腺功能与血脂异常之间的关联在观察性研究中已有充分的记载。然而，观察性研究容易受到混杂因素的影响，因此很难进行因果推断。我们使用大规模全基因组关联研究的甲状腺刺激激素（TSH）、游离 T4（FT4）和血脂的汇总统计数据进行了两样本双向孟德尔随机化（MR）。我们选择逆方差加权（IVW）方法进行主要分析，并通过在不同模型规范下涉及 6 种不同 MR 方法的各种敏感性分析来整合结果。我们进一步进行了遗传相关分析和共定位分析，以深入反映因果关系。IVW 方法表明，正常 TSH 每增加 1 个 SD，总胆固醇（TC）就会显著增加 0.048 SD（P<0.001），低密度脂蛋白胆固醇（LDL）增加 0.032 SD（P=0.021）。正常 FT4 增加 1 SD，TC 显著降低 0.056 SD（P=0.014），LDL 降低 0.072 SD（P=0.009）。TSH 或 FT4 与高密度脂蛋白胆固醇和甘油三酯均无因果关系。未检测到血脂对正常 TSH 或 FT4 的因果影响。当使用几种替代 MR 方法时，所有结果均基本一致，并且通过遗传相关分析和共定位分析也得到了证实。我们的研究表明，即使在参考范围内，较高的 TSH 或较低的 FT4 与 TC 和 LDL 的增加也存在因果关系，而不能发现相反的因果关系。
