Mendelian randomization links CETP inhibition to lower lacunar stroke risk via cerebral small vessel disease genetics (Brain 2025)

Cerebral small vessel disease (cSVD) causes lacunar stroke (LS) and intracerebral haemorrhage and is the most common pathology underlying vascular dementia. However, there are few trials examining whether treatment of conventional cardiovascular risk factors reduces stroke risk in cSVD, as opposed to stroke as a whole. We used Mendelian randomization techniques to investigate which risk factors are causally related to cSVD and to evaluate whether specific drugs might be beneficial in cSVD prevention. We identified genetic proxies for blood pressure traits, lipids, glycaemic markers, anthropometry measures, smoking, alcohol consumption and physical activity from large-scale genome-wide association studies of European ancestry. We also selected genetic variants as proxies for drug target perturbation in hypertension, dyslipidaemia, hyperglycaemia and obesity. Mendelian randomization was performed to assess their associations with LS from the GIGASTROKE Consortium (n = 6811) and in a sensitivity analysis in a cohort of patients with MRI-confirmed LS (n = 3306). We also investigated associations with three neuroimaging features of cSVD, namely, white matter hyperintensities (n = 55 291), fractional anisotropy (n = 36 460) and mean diffusivity (n = 36 012). Genetic predisposition to higher systolic and diastolic blood pressure was associated with LS and cSVD imaging markers. Genetically predicted liability to diabetes, obesity, smoking, higher triglyceride levels and the ratio of triglycerides to high-density lipoprotein also showed detrimental associations with LS risk, whereas genetic predisposition to higher high-density lipoprotein concentrations and moderate-to-vigorous physical activity showed protective associations. Genetically proxied blood pressure lowering through calcium channel blockers was associated with cSVD imaging markers, whereas genetically proxied high-density lipoprotein raising through cholesteryl ester transfer protein inhibitors, triglyceride lowering through lipoprotein lipase and weight lowering through gastric inhibitory polypeptide receptor were associated with lower risk of LS. Our findings highlight the importance of some conventional cardiovascular risk factors, including blood pressure and body mass index, in cSVD, but not others, e.g. low-density lipoprotein. The findings also demonstrate the potential beneficial effects of calcium channel blockers on cSVD imaging markers and cholesteryl ester transfer protein inhibitors, lipoprotein lipase enhancement and gastric inhibitory polypeptide receptor obesity-targeted drugs on LS. They provide useful information for initiating future clinical trials examining secondary prevention strategies in cSVD.