孟德尔随机化
医学
冲程(发动机)
优势比
内科学
PCSK9
白质
心脏病学
脑出血
病理
胆固醇
磁共振成像
脂蛋白
低密度脂蛋白受体
放射科
基因型
遗传学
生物
机械工程
遗传变异
基因
工程类
蛛网膜下腔出血
作者
Marie‐Joe Dib,Loukas Zagkos,Devendra Meena,Stephen Burgess,Julio A. Chirinos,Dipender Gill
出处
期刊:Stroke
[Ovid Technologies (Wolters Kluwer)]
日期:2024-06-01
卷期号:55 (6): 1676-1679
标识
DOI:10.1161/strokeaha.123.045297
摘要
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.
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