Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage.
Falcone GJ., Kirsch E., Acosta JN., Noche RB., Leasure A., Marini S., Chung J., Selim M., Meschia JF., Brown DL., Worrall BB., Tirschwell DL., Jagiella JM., Schmidt H., Jimenez-Conde J., Fernandez-Cadenas I., Lindgren A., Slowik A., Gill D., Holmes M., Phuah C-L., Petersen NH., Matouk Md CN., Gunel M., Sansing L., Bennett D., Chen Z., Sun LL., Clarke R., Walters RG., Gill TM., Biffi A., Kathiresan S., Langefeld CD., Woo D., Rosand J., Sheth KN., Anderson CD., International Stroke Genetics Consortium None.
OBJECTIVE: Observational studies point to an inverse correlation between low-density lipoprotein (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, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (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 (MR) 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). MR analyses indicated that 1mmol/L (38.67mg/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. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.