Abdominal Adiposity and Lacunar Stroke: A Mendelian Randomization Mediation Study
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Background
Lacunar stroke accounts for approximately 25% of ischaemic strokes and is linked to metabolic and vascular risk factors. Abdominal adiposity, measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI), is a heritable predictor of cerebrovascular disease independent of overall adiposity, but its biological mediators remain unclear. We performed a two-sample Mendelian randomization (MR) mediation analysis of 16 candidate biomarkers.
Methods
Summary-level GWAS data were obtained from the IEU Open GWAS and EBI GWAS Catalog for WHRadjBMI (exposure), 16 mediators, and lacunar stroke (outcome). Instruments met genome-wide significance (P < 5 × 10⁻⁸), LD clumping (r² < 0.001, 10,000 kb; 1000 Genomes European panel), and F-statistic ≥ 10. Inverse variance weighted regression was the primary analysis, with MR-Egger, weighted median, and MR-PRESSO sensitivity analyses. Mediation was quantified using the product-of-coefficients method with delta-method standard errors.
Results
Systolic blood pressure showed the largest mediation proportion (29.6%; 95% CI, 12.7%–46.5%), followed by diastolic blood pressure (29.2%; 12.1%–46.3%) and glycated hemoglobin (23.0%; −11.2% to 57.2%). Other mediators included triglycerides (10.8%), fasting insulin (9.9%), blood glucose (7.0%), HDL cholesterol (3.2%), and LDL cholesterol (1.1%). Sensitivity analyses were generally consistent, though MR-Egger intercepts suggested directional pleiotropy for glycoprotein acetyls and CRP (Path A only). Because mediators are intercorrelated, proportions cannot be summed; multivariable MR is needed for joint effects. The HbA1c estimate was imprecise and requires cautious interpretation.
Conclusions
Blood pressure, and possibly glycemic control, are the leading mediators linking abdominal adiposity to lacunar stroke. These findings support prioritizing blood pressure management—and potentially glycemic control—to reduce small vessel cerebrovascular disease in individuals with elevated WHRadjBMI.
Trial registration
Not applicable.
