Thyroid function and hypertensive disorders of pregnancy: Insights from a sex-specific cohort study, Mendelian randomization, and experimental validation.
OBJECTIVE To investigate the association of a history of hypertensive disorders of pregnancy (HDP) and a higher risk of cardiovascular disease using a sex-specific cohort study, bidirectional two-sample Mendelian randomization (MR), and in vitro experiments. METHODS Multivariable logistic regression was used to assess the association between thyroid function and HDP. We performed bidirectional two-sample MR using summary statistics from genome-wide association study meta-analyses, FinnGen, and UKB to assess the potential association between thyroid function and HDP. In vitro experiments were conducted to explore the potential biologic mechanisms underlying the observed association. RESULTS In the cohort (n = 119 668), hyperthyroidism was associated with higher HDP risk (odds ratio [OR] 1.79, 95% confidfence interval [CI] 1.10-2.92, P = 0.020; fully adjusted for confounders). MR identified a potential association of genetically predicted thyroid-stimulating hormone (TSH) on HDP (OR 0.92, 95% CI 0.85-0.99, P = 0.018), but no evidence was found to support a causal effect of hypothyroidism, hyperthyroidism, or free thyroxine on HDP. Reverse MR indicated that genetically predicted pre-eclampsia was associated with elevated TSH levels (β 0.12, 95% CI 0.05-0.19, P < 0.001). In vitro experiments confirmed and provided supportive mechanistic evidence that TSH may directly induce vascular endothelial injury and dysfunction. CONCLUSION This study demonstrates an independent observational association between hyperthyroidism and an increased risk of HDP, and provides supportive genetic evidence for a possible bidirectional association between genetically predicted TSH and HDP. These findings highlight TSH as a potential biomarker for HDP risk stratification.