Genetically Elevated Selenoprotein S Levels and Risk of Stroke: A Two-Sample Mendelian Randomization Analysis

Selenoprotein S (SELENOS), one of the carrier proteins of dietary selenium (Se), is a key regulator of inflammation, oxidative stress, and endoplasmic reticulum (ER) stress, all of which are implicated in the pathogenesis of stroke. However, the causality between SELENOS and stroke risk remains poorly understood. This study aimed to explore the association between genetically determined plasma SELENOS levels and the risk of all-cause stroke, ischemic stroke, and intracerebral hemorrhage (ICH) using a two-sample Mendelian randomization (MR) approach. We analyzed data from three large-scale Genome-Wide Association Study (GWAS) meta-analyses of individuals of European descent. The fixed-effect inverse-variance weighted (IVW) model analysis revealed that genetically elevated SELENOS levels were associated with an increased risk of all-cause stroke, ischemic stroke, and ICH. Sensitivity analyses showed no evidence of pleiotropy or heterogeneity, and leave-one-out analyses confirmed the robustness of our results. Here, we show that elevated plasma SELENOS levels are causally linked to increased stroke risk. Although the effect sizes were modest, these findings suggest SELENOS may play a role in stroke pathogenesis, emphasizing the need for further mechanistic and functional studies. Finally, our findings shed light on the importance of tailored Se intake management in the context of stroke prevention.