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LDL-c Lowering, Ischemic Stroke, and Small Vessel Disease Brain Imaging Biomarkers: A Mendelian Randomization Study.

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Meena, Devendra 
Burgess, Stephen 


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.



Mendelian randomization analysis, genetics, ischemic stroke, lipid-lowering drugs, stroke, Humans, Mendelian Randomization Analysis, Ischemic Stroke, Cholesterol, LDL, Cerebral Small Vessel Diseases, Proprotein Convertase 9, Biomarkers, Membrane Transport Proteins, Hydroxymethylglutaryl CoA Reductases, Brain, Membrane Proteins, Genome-Wide Association Study, Female

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Ovid Technologies (Wolters Kluwer Health)
Wellcome Trust (225790/Z/22/Z)