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Genetically predicted on-statin LDL response is associated with higher intracerebral hemorrhage risk

By Ernst Mayerhofer, Rainer Malik, Livia Parodi, Stephen Burgess, Andreas Harloff, Martin Dichgans, Jonathan Rosand, Christopher D Anderson, Marios K Georgakis

Posted 23 Mar 2022
medRxiv DOI: 10.1101/2022.03.22.22272697

Statins lower low-density lipoprotein (LDL) cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced LDL reduction increases risk of intracerebral hemorrhage (ICH) has been debated for almost two decades. Here, we explored whether genetically predicted LDL response to statins is associated with ICH risk using Mendelian Randomization. Utilizing genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms (SNP) of on-statin LDL response and tested it in the population-based UK-Biobank (UKB). We extracted statin drug and dose data from primary care data on a subset of UKB participants covering a period of 29 years (225,195 individuals). We validated the effects of the genetic score on longitudinal LDL measurements with generalized mixed models and explored associations with incident ICH using Cox regression analysis. Statins were prescribed at least once to 75,973 (31%) of the study participants (mean 57 years, 55% females). Among statin users, mean LDL decreased by 3.45 mg/dl per year (95% CI: [-3.47, -3.42]) over follow-up. A higher genetic score of statin response (one SD increment) was associated with significant additional reductions in LDL levels (-0.05 mg/dl per year, [ 0.07, -0.02]), showed concordant lipidomic effects on other lipid traits as statin use, and was associated with a lower risk for incident myocardial infarction (HR per SD increment 0.98 95% CI [0.96, 0.99]) and peripheral artery disease (HR per SD increment 0.92 95% CI [0.86, 0.98]). Over a 14-year follow-up period, a higher genetically predicted statin response among statin users was associated with increased ICH risk (HR per SD increment 1.15, 95% CI [1.04, 1.27]) in a model adjusting for statin dose whereas there was no association with ICH risk among statin non-users, (p=0.89). On-statin genetically predicted LDL response is associated with ICH. This provides further support for the hypothesis that LDL reduction is causally associated with ICH risk. While the net benefit of statins for preventing vascular disease is well-established, these results provide insights about the personalized response to statin intake and the role of pharmacologic LDL-lowering in the pathogenesis of ICH.

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