Assessing the effects of HMGCR and LDLR Inhibition on multiple stroke types: A trans-ancestry drug-target Mendelian randomization study

BACKGROUND AND AIMS: While statins are established to reduce overall ischemic stroke risk, their effects on ischemic stroke subtypes (AS= any stroke, AIS= any ischemic stroke, CES= cardioembolic stroke, LAS= large artery stroke, SVS= small vessel stroke), intracerebral hemorrhage (ICH) and cerebral microbleeds (CMBs) remain poorly characterized. This study aims to disentangle the distinct causal effects of HMGCR inhibition on multiple stroke types, while concurrently evaluating LDLR as an alternative therapeutic target. METHODS AND RESULTS: Genetic variants were extracted from datasets by the Global Lipids Genetics Consortium and the UK Biobank Consortium. Various Mendelian randomization (MR) approaches, including IVW, MR-RAPS, cML-MA, and BWMR, were used for primary and complementary analyses. HMGCR inhibition significantly reduced the risk of SVS (GLGC: OR [95 %Cl]: 0.50 [0.36 to 0.70] p < 0.001, UKB: 0.47 [0.33 to 0.67] p < 0.001) and All CMBs (GLGC: OR [95 %Cl]: 0.43 [0.29 to 0.65] p < 0.001, UKB: 0.41 [0.26 to 0.65] p < 0.001). Weak evidence showed that HMGCR inhibition may be linked to an elevated risk of ICH (GLGC: OR [95 %Cl]: 1.67 [1.16 to 2.39] p = 0.005, UKB: 1.58 [1.09 to 2.29] p = 0.015). In contrast, LDLR inhibition significantly increased the risk of AS (GLGC: OR [95 %Cl]: 1.31 [1.14 to 1.51] p < 0.001, UKB: 1.32 [1.15 to 1.51] p < 0.001), but reduced the risk of AS in East-Asians (OR [95 %Cl]: 0.78 [0.67 to 0.92] p = 0.002). CONCLUSION: HMGCR inhibition provides subtype-specific benefits for small vessel ischemic stroke and CMBs but carries a trade-off risk for ICH. LDLR inhibition may have differential effects across ancestries, warranting further validation. These findings provide genetic evidence to guide precision use of statins and novel LDLR-targeted therapies.