Abstract
Background: Observational studies found an inverse correlation between cholesterol levels and risk of spontaneous intracerebral hemorrhage (ICH). We investigated whether the cumulative burden of known genetic risk loci for cholesterol levels influences the risk of sustaining an ICH. Methods: We utilized genetic risk scores (GRSs) to model the cumulative burden of cholesterol-related common genetic variants (CGVs). GRSs were constructed using an approach that allows the implementation of GRS analysis by combining summary statistics from GCVs known to influence the exposure (cholesterol levels) and outcome (ICH) of interest. Summary statistics were identified and abstracted using the Cerebrovascular Disease Knowledge Portal. For cholesterol levels (derivation dataset), we abstracted summary statistics for independent CGVs associated with cholesterol levels at p<5x10 -5 in a large genetic meta-analysis that included data from Kaiser Permanente, UK Biobank and Global Lipids Genetics Consortium. We excluded CGVs at CETP , a cholesterol-related locus known to modify ICH risk. For ICH (testing dataset), we abstracted summary statistics from a meta-analysis of 5 genetic studies. Results: We identified 711 CGVs associated with cholesterol levels in the derivation dataset (study population 76,627, mean age 56 [SD 9], female sex 44,856 [59%]). Summary statistics were available for 468 of these CGVs in the ICH testing dataset (study population 3,026, mean age 67 [SD 10], female sex 1,362 [45%]). The GRSs for total cholesterol (OR 0.87, 95%CI 0.73-1.01; p =0.04), LDL (OR 0.78, 95%CI 0.65-0.91; p =0.0002) and triglycerides (OR 1.18, 95%CI 1.04-1.32; p =0.02) were associated with risk of all ICH. After stratifying by location, the association became stronger for deep ICH and total cholesterol (OR 0.77, 95%CI 0.61-0.93; p =0.001) and LDL (OR 0.70, 95%CI 0.55-0.85; p =8x10 -6 ). Only the triglycerides-based GRS was associated with lobar ICH (OR 1.26, 95%CI 1.08-1.44; p =0.01). Conclusions: The cumulative burden of cholesterol-related mutations is associated with risk of ICH. Our results point to an inverse correlation between genetically-determined total cholesterol and LDL levels and ICH risk. These associations are stronger for deep ICH.
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