Selenoprotein S and the Causal Risk of Hypertension in Pregnancy: A Mendelian Randomization Study

<b>Background:</b> Pregnancy-induced hypertension (PIH) affects approximately 10% of pregnancies worldwide, representing a leading cause of maternal and perinatal morbidity and mortality. The relationship between plasma selenium levels and PIH remains controversial, with observational studies limited by confounding factors. Selenoprotein S (SELENOS) has emerged as a potential biomarker for PIH risk. As one of the carrier proteins for dietary selenium, SELENOS plays a crucial role in oxidative stress and inflammatory pathways. However, the causal relationship between the plasma levels of the SELENOS and PIH development remains unclear. This study employed Mendelian randomization (MR) to investigate the causal link between the plasma levels of the SELENOS and PIH risk, providing evidence for preventive strategies. <b>Methods:</b> We conducted a two-sample MR analysis using genome-wide association study (GWAS) summary statistics from the INTERVAL study and FinnGen consortium. The analysis included individuals of European ancestry, utilizing the inverse-variance weighted (IVW) method as the primary approach. Comprehensive sensitivity analyses were performed to address potential pleiotropy and strengthen causal inference. <b>Results:</b> The analysis encompassed 3301 samples for the plasma levels of the SELENOS and 7686 PIH cases, 1109 pre-existing hypertension (PEH) cases, 4255 gestational hypertension (GH) cases, and 83 preeclampsia (PE) cases superimposed on chronic hypertension, alongside approximately 115,000 controls. Genetic variabilities that have been found to be accompanied by elevated levels of plasma selenioprotein levels showed significant associations with increased risk of PIH [odds ratio (OR) 1.078, 95% confidence interval (CI) 1.031-1.126, <i>p</i> = 0.001], PEH (OR 1.232, 95% CI 1.105-1.373, <i>p</i> < 0.001), and GH (OR 1.111, 95% CI 1.047-1.180, <i>p</i> = 0.001), with suggestive associations for preeclampsia superimposed on chronic hypertension (OR 1.590, 95% CI 1.078-2.344, <i>p</i> = 0.019). <b>Conclusions:</b> This study provides robust genetic evidence for a causal relationship between the plasma levels of the SELENOS and PIH risk, establishing SELENOS as a potential modifiable risk factor with significant clinical implications. These findings support the development of personalized selenium management strategies during pregnancy and highlight the potential for early screening and targeted interventions to improve maternal and fetal outcomes.