| Title: | Genetically predicted on-statin LDL response is associated with higher intracerebral haemorrhage risk |
| Journal: | Brain |
| Published: | 22 May 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35598204/ |
| DOI: | https://doi.org/10.1093/brain/awac186 |
| URL: | https://academic.oup.com/brain/article-pdf/145/8/2677/46659352/awac186.pdf |
| Citations: | 17 (15 in last 2 years) as of 8 Aug 2024 |
Publication 12365
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Abstract
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.</p>
8 Keywords
- Cerebral Hemorrhage
- Cholesterol, LDL
- Female
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
- Male
- Myocardial Infarction
- Risk Factors
9 Authors
- Ernst Mayerhofer
- Rainer Malik
- Livia Parodi
- Stephen Burgess
- Andreas Harloff
- Martin Dichgans
- Jonathan Rosand
- Christopher D Anderson
- Marios K Georgakis
1 Application
| Application ID | Title |
|---|---|
| 36993 | Identification of genetic components underlying cerebrovascular diseases and their related outcomes |
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