{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Dib MJ"],"funding":["British Heart Foundation"],"pagination":["1676-1679"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7615976"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["55(6)"],"pubmed_abstract":["<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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]).<h4>Conclusions</h4>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."],"journal":["Stroke"],"pubmed_title":["LDL-c Lowering, Ischemic Stroke, and Small Vessel Disease Brain Imaging Biomarkers: A Mendelian Randomization Study."],"pmcid":["PMC7615976"],"funding_grant_id":["RE/18/4/34215"],"pubmed_authors":["Gill D","Meena D","Zagkos L","Burgess S","Chirinos JA","Dib MJ"],"additional_accession":[]},"is_claimable":false,"name":"LDL-c Lowering, Ischemic Stroke, and Small Vessel Disease Brain Imaging Biomarkers: A Mendelian Randomization Study.","description":"<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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]).<h4>Conclusions</h4>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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jun","modification":"2025-04-05T15:03:26.433Z","creation":"2025-04-05T15:03:26.433Z"},"accession":"S-EPMC7615976","cross_references":{"pubmed":["38572634"],"doi":["10.1161/STROKEAHA.123.045297"]}}