Statins and hemorrhagic stroke: New insight from a Mendelian randomization study

The relationship between statin usage and hemorrhagic stroke (HS) has been reported in clinical studies, but the link was contradictory and causality from statin usage to HS remained unclarified. We aimed to investigate statin's causal effects of blood and brain on HS risk with the Summary-data-based Mendelian randomization (SMR) method. We used 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) gene expression-associated single-nucleotide polymorphisms (SNPs) to proxy the pleiotropic effects of statin. Comparison analysis was performed to explore the difference between blood and the brain in the pattern of HMGCR affecting HS and HMGCR gene expression. SMR analysis found that a higher blood HMGCR expression decreased the risk of subarachnoid hemorrhage (SAH) (OR = 0.64, 95% CI = 0.43-0.95, SMR-P = .027), while brain HMGCR gene expression increased the risk of SAH at a boundary significance (OR = 1.11, 95% CI = 1.00-1.23, SMR-P = .049). Comparison analysis showed a negative relationship between blood and brain in the pattern of HMGCR affecting HS and HMGCR gene expression. This MR study suggested that HMGCR expression in the brain increased HS risk. The controversial results from the blood data were due to the difference in HMGCR gene expression between the brain and blood. Lipophilic statins might benefit patients more from the lower HS risk than the hydrophilic ones.