Metabolic Factors Mediate the Causal Effect of Physical Activity and Sedentary Behavior on Stroke and Its Subtypes:...

In observational studies, physical activity and sedentary behavior are associated with the risk of stroke (overall and stroke subtypes). However, whether it is causal relevance remains to be established. Given that exercise habits can be an intervention towards preventing strokes, we assessed the causality of behavioral habits with stroke and its subtypes using Mendelian randomization (MR) approaches. Stroke was analyzed as all-cause ischemic stroke (IS), three IS subtypes including large artery stroke, small vessel stroke and cardioembolic stroke, and intracerebral hemorrhage (ICH). Univariable MR analyses revealed an association between genetically predicted leisure screen time and higher overall IS risk (odds ratio (OR), 1.12; 95% confidence interval (CI), 1.06 to 1.19; P = 1.65 × 10^-4). A protective association was also reported between genetically linked moderate-to-vigorous intensity physical activity and the risk of small vessel stroke (OR, 0.52; 95% CI, 0.32 to 0.84; P = 0.008). Further reverse analyses found no causal effect of IS on leisure screen time and small vessel stroke on moderate-to-vigorous intensity physical activity. We also studied the mediating role of metabolic traits including obesity, blood lipids, blood glucose, and blood pressure via two-step MR. It was found in mediation analysis that BMI partly mediated the causal relationship between leisure screen time and all-cause IS; the mediated proportion was 26.1% (95% CI: 18.1 to 35.0%). We found evidence that a sedentary lifestyle is associated with a higher risk of overall IS, and BMI plays a mediating role in the causal pathway. Our findings provide genetic evidence for the point that active lifestyles may be an effective prevention strategy for IS.