Using two-sample Mendelian randomization mediation analysis across 16 candidate biomarkers, abdominal adiposity—measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI)—was found to increase lacunar stroke risk predominantly through blood pressure pathways. Systolic blood pressure mediated 29.6% (95% CI: 12.7%–46.5%) of the effect, diastolic blood pressure mediated 29.2%, and glycated hemoglobin accounted for 23.0%. Secondary mediators included triglycerides (10.8%), fasting insulin (9.9%), fasting glucose (7.0%), and HDL cholesterol (3.2%), though these estimates carry greater uncertainty.
Lacunar stroke—caused by small vessel disease and representing roughly one-quarter of all ischaemic strokes—has long been associated with hypertension and metabolic dysfunction, but the relative contributions of specific biological pathways remained poorly quantified. By leveraging genetic instruments as proxies for lifetime exposure, Mendelian randomization sidesteps confounding that plagues observational studies, offering stronger causal inference. The finding that blood pressure alone explains nearly 60% of the adiposity-to-lacunar stroke pathway reinforces decades of clinical evidence prioritizing antihypertensive therapy in metabolically obese patients—but now with cleaner mechanistic grounding.
Limitations are meaningful: analyses rely exclusively on European-ancestry GWAS data, limiting generalizability; mediator intercorrelations prevent summing proportions; the HbA1c estimate is flagged as imprecise; and pleiotropy signals emerged for glycoprotein acetyls and CRP. Critically, this is a preprint posted on medRxiv and has not yet undergone peer review—findings should be interpreted cautiously until independently validated. Overall, the work is confirmatory but usefully quantitative, strengthening the case for aggressive blood pressure control in abdominally obese individuals.
