LDL-c lowering, ischemic stroke, and small vessel disease brain imaging biomarkers: a Mendelian randomization study
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
BACKGROUND: The effects of lipid-lowering drug targets on different ischemic stroke subtypes are not fully understood. We aimed to explore the mechanisms by which lipid-lowering drug targets differentially affect the risk of ischemic stroke subtypes and their underlying pathophysiology. METHODS: Using a 2-sample Mendelian randomization approach, we assessed the effects of genetically proxied low-density lipoprotein cholesterol (LDL-c) and 3 clinically approved LDL-lowering drugs (HMGCR [3-hydroxy-3-methylglutaryl-CoA reductase], PCSK9 [proprotein convertase subtilisin/kexin type 9], and NPC1L1 [Niemann-Pick C1-Like 1]) on stroke subtypes and brain imaging biomarkers associated with small vessel stroke (SVS), including white matter hyperintensity volume and perivascular spaces. RESULTS: In genome-wide Mendelian randomization analyses, lower genetically predicted LDL-c was significantly associated with a reduced risk of any stroke, ischemic stroke, and large artery stroke, supporting previous findings. Significant associations between genetically predicted LDL-c and cardioembolic stroke, SVS, and biomarkers, perivascular space and white matter hyperintensity volume, were not identified in this study. In drug-target Mendelian randomization analysis, genetically proxied reduced LDL-c through NPC1L1 inhibition was associated with lower odds of perivascular space (odds ratio per 1-mg/dL decrease, 0.79 [95% CI, 0.67-0.93]) and with lower odds of SVS (odds ratio, 0.29 [95% CI, 0.10-0.85]). CONCLUSIONS: This study provides supporting evidence of a potentially protective effect of LDL-c lowering through NPC1L1 inhibition on perivascular space and SVS risk, highlighting novel therapeutic targets for SVS.
Date Issued
2024-06
Date Acceptance
2024-03-13
Citation
Stroke, 2024, 55 (6), pp.1676-1679
ISSN
0039-2499
Publisher
Lippincott, Williams & Wilkins
Start Page
1676
End Page
1679
Journal / Book Title
Stroke
Volume
55
Issue
6
Copyright Statement
Copyright © 2024 American Heart Association, Inc. This is the author’s accepted manuscript made available under a CC-BY licence in accordance with Imperial’s Research Publications Open Access policy (www.imperial.ac.uk/oa-policy)
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/38572634
Subjects
Biomarkers
Brain
Cerebral Small Vessel Diseases
Cholesterol, LDL
Female
Genome-Wide Association Study
Humans
Hydroxymethylglutaryl CoA Reductases
Ischemic Stroke
Membrane Proteins
Membrane Transport Proteins
Mendelian Randomization Analysis
Proprotein Convertase 9
genetics
ischemic stroke
lipid-lowering drugs
Mendelian randomization analysis
stroke
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2024-04-04