Variation in Normal Range Thyroid Function Affects Serum Cholesterol Levels, Blood Pressure, and Type 2 Diabetes Risk: A Mendelian Randomization Study

Abstract

Background: Observational studies have demonstrated that variation in normal range thyroid function is associated with major cardiovascular risk factors, including dyslipidemia, hypertension, type 2 diabetes (T2D), and obesity. As observational studies are prone to residual confounding, reverse causality, and selection bias, we used a Mendelian randomization (MR) approach to investigate whether these associations are causal or not. Methods: Two-sample MR analysis using data from the largest available genome-wide association studies on normal range thyrotropin (TSH) and free thyroxine (fT4) levels, serum lipid levels, blood pressure measurements, T2D, and obesity traits (body mass index [BMI] and waist/hip ratio). Results: A one standard deviation (SD) increase in genetically predicted TSH levels was associated with a 0.037 SD increase in total cholesterol levels (p = 3.0 • 10-4). After excluding pleiotropic instruments, we also observed significant associations between TSH levels and low-density lipoprotein levels (b = 0.026 SD, p = 1.9 • 10-3), pulse pressure (b =-0.477 mmHg, p = 7.5 • 10-10), and T2D risk (odds ratio = 0.95, p = 2.5 • 10-3). While we found no evidence of causal associations between TSH or fT4 levels and obesity traits, we found that a one SD increase in genetically predicted BMI was associated with a 0.075 SD decrease in fT4 levels (p = 3.6 • 10-4). Conclusions: Variation in normal range thyroid function affects serum cholesterol levels, blood pressure, and T2D risk.

Causal Association Between Serum Thyrotropin and Obesity: A Bidirectional, Mendelian Randomization Study

“…Therefore, MR is an ideal method when we need to explore the causal relationship between different indicators. A recently published MR study analyzed the causality between thyroid function and cardiovascular risk factors such as blood pressure, blood lipids, diabetes, and obesity traits ( 49 ). The authors found no significant evidence of causal associations between genetically predicted TSH and BMI, or vice versa.…”

Update on dyslipidemia in hypothyroidism: the mechanism of dyslipidemia in hypothyroidism

“…A higher degree of ApoB-containing lipoprotein cholesterols is found in patients with TSH >10 mLU/L compared to those with TSH 4.0–10.0 mLU/L ( 17 , 18 , 19 ). Regardless of the thyroid status, circulating TSH level is always positively correlated with levels of ApoB-containing lipoprotein cholesterols ( 20 , 21 , 22 , 23 , 24 , 25 ). Hence the higher TSH level is, the greater the risks of dyslipidemia are ( 26 ).…”

Thyroid Function and the Risk of Prediabetes and Type 2 Diabetes

“…However, Bos and colleagues did find an association between genetic variants related to thyroid metabolism and insulin resistance ( 35 ), supporting a potential role of thyroid function in the pathogenesis of type 2 diabetes. A more recent mendelian randomization study by Kuś et al ( 36 ) found no association between thyroid hormones and type 2 diabetes in their main analyses, but when pleiotropic instruments were excluded, they observed that greater levels of TSH were statistically significantly associated with lower risk of type 2 diabetes. More research is needed to reconcile the differences between observational studies and mendelian randomization studies by exploring potential underlying mechanisms (eg, mediation analyses) and through an increase in genetic instruments for hypothyroidism and hyperthyroidism as well as TSH and FT4 (eg, larger explained genetic variability).…”

“…Two previous mendelian randomization studies have been performed with conflicting results ( 35 , 36 ). The first by Bos et al ( 35 ) found no association between TSH/FT4 with type 2 diabetes, suggesting that the association reported by traditional observational studies could be due to reverse causation or unmeasured confounding ( 35 ).…”