Genetically Predicted On-statin LDL Response Is Associated With Higher Intracerebral Haemorrhage Risk

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


Brain. 2022;145(8):2677-2686. 

In This Article

Abstract and Introduction


Statins lower low-density lipoprotein cholesterol and are widely used for the prevention of atherosclerotic cardiovascular disease. Whether statin-induced low-density lipoprotein reduction increases risk of intracerebral haemorrhage has been debated for almost two decades. Here, we explored whether genetically predicted on-statin low-density lipoprotein response is associated with intracerebral haemorrhage risk using Mendelian randomization. Using genomic data from randomized trials, we derived a polygenic score from 35 single nucleotide polymorphisms of on-statin low-density lipoprotein response and tested it in the population-based UK Biobank. We extracted statin drug and dose information from primary care data on a subset of 225 195 UK Biobank participants covering a period of 29 years. We validated the effects of the genetic score on longitudinal low-density lipoprotein measurements with generalized mixed models and explored associations with incident intracerebral haemorrhage 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 low-density lipoprotein decreased by 3.45 mg/dl per year [95% confidence interval (CI): (−3.47, −3.42)] over follow-up. A higher genetic score of statin response [1 standard deviation (SD) increment] was associated with significant additional reductions in low-density lipoprotein 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 [hazard ratio per SD increment 0.98 95% CI (0.96, 0.99)] and peripheral artery disease [hazard ratio per SD increment 0.93 95% CI (0.87, 0.99)]. Over a 11-year follow-up period, a higher genetically predicted statin response among statin users was associated with higher intracerebral haemorrhage risk in a model adjusting for statin dose [hazard ratio per SD increment 1.16, 95% CI (1.05, 1.28)]. On the contrary, there was no association with intracerebral haemorrhage risk among statin non-users (P = 0.89). These results provide further support for the hypothesis that statin-induced low-density lipoprotein reduction may be causally associated with intracerebral haemorrhage 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 pharmacological low-density lipoprotein lowering in the pathogenesis of intracerebral haemorrhage.


Intracerebral haemorrhage (ICH) is a devastating disease associated with a 50% 30-day mortality and major disability among survivors.[1,2] HMG-CoA-reductase inhibitors, commonly known as statins, reduce low-density lipoprotein (LDL) and are widely used for prevention of atherosclerotic cardiovascular disease.[3] The role of LDL in the pathogenesis of ICH, and whether statin intake increases ICH risk, has been a matter of continued debate[4,5] with conflicting data from observational studies and post hoc analyses of clinical trials.[5–20]

Human genetic data are a valuable resource for unravelling the role of specific mechanisms in the pathogenesis of diseases. Because genetic liability to polygenic traits is randomly assigned at birth, using genetic variants that are reliably associated with a trait of interest but do not vary with correlated confounders can reduce bias in associations between genetically predicted traits and outcomes.[21–25] Applying this framework, called Mendelian randomization (MR), previous studies have explored whether genetically predicted levels of lipids influence the risk of ICH.[26–29] However, these findings do not address the specific question of whether statin-induced LDL lowering actually increases ICH risk, because the genetic variants capture lifelong small effects on blood lipid levels and not the much stronger short-term effects that result from taking a medication in adulthood.

Expanding the MR concept, genetic variants associated with response to a drug could be used for stratification of individuals in observational studies. Because the innate drug sensitivity is unknown to physicians at the time of prescription, it could be used as instrument for randomizing participants to different levels of drug exposure. This could determine dose-dependent effects of specific drugs on potential side-effects or for exploring repurposing opportunities with the use of observational data, thus overcoming key limitations of conventional MR analyses.[30] In this study, we applied this concept to study the relationship between statin use and ICH risk by leveraging large-scale genetic data for on-statin LDL response from clinical trials and population-based observational data from the UK Biobank (UKB).