Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.

OBJECTIVE: Observational studies point to an inverse correlation between LDL cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically-elevated LDL is associated with reduced risk of ICH. METHODS: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, HDL and triglycerides) using independent genome-wide significant SNPs for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization analyses. RESULTS: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p 0.05). Mendelian Randomization analyses indicated that 1 mmol/L (38.67 mg/dL) increase of genetically-instrumented total and LDL cholesterol were associated with 23% (OR 0.77; 95%CI 0.65-0.98; p=0.03) and 41% lower risks of ICH (OR 0.59; 95%CI 0.42-0.82; p=0.002), respectively. INTERPRETATION: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. This article is protected by copyright. All rights reserved.