Assessment of causal direction between thyroid function and cardiometabolic health: a Mendelian randomization study

BACKGROUND Growing evidence have demonstrated that thyroid hormones have been involved in the processes of cardiovascular metabolism. However, the causal relationship of thyroid function and cardiometabolic health remains partly unknown. METHODS The Mendelian randomization (MR) was used to test genetic, potentially causal relationships between instrumental variables and cardiometabolic traits. Genetic variants of free thyroxine (FT4) and thyrotropin (TSH) levels within the reference range were used as instrumental variables. Data for genetic associations with cardiometabolic diseases were acquired from the genome-wide association studies of the FinnGen, CARDIoGRAM and CARDIoGRAMplusC4D, CHARGE, and MEGASTROKE. This study was conducted using summary statistic data from large, previously described cohorts. Association between thyroid function and essential hypertension (EHTN), secondary hypertension (SHTN), hyperlipidemia (HPL), type 2 diabetes mellitus (T2DM), ischemic heart disease (IHD), myocardial infarction (MI), heart failure (HF), pulmonary heart disease (PHD), stroke, and non-rheumatic valve disease (NRVD) were examined. RESULTS Genetically predicted FT4 levels were associated with SHTN (odds ratio = 0.48; 95% CI = 0.04-0.82, P = 0.027), HPL (odds ratio = 0.67; 95% CI = 0.18-0.88, P = 0.023), T2DM (odds ratio = 0.80; 95% CI = 0.42-0.86, P = 0.005), IHD (odds ratio = 0.85; 95% CI = 0.49-0.98, P = 0.039), NRVD (odds ratio = 0.75; 95% CI = 0.27-0.97, P = 0.039). Additionally, genetically predicted TSH levels were associated with HF (odds ratio = 0.82; 95% CI = 0.68-0.99, P = 0.042), PHD (odds ratio = 0.75; 95% CI = 0.32-0.82, P = 0.006), stroke (odds ratio = 0.95; 95% CI = 0.81-0.97, P = 0.007). However, genetically predicted thyroid function traits were not associated with EHTN and MI. CONCLUSIONS Our study suggests FT4 and TSH are associated with cardiometabolic diseases, underscoring the importance of the pituitary-thyroid-cardiac axis in cardiometabolic health susceptibility.