{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T12:23:46Z","timestamp":1792844626593,"version":"4.5.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T00:00:00Z","timestamp":1732838400000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["R79992\/CN001"],"award-info":[{"award-number":["R79992\/CN001"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014013","name":"UKRI","doi-asserted-by":"publisher","award":["ES\/P011055\/1"],"award-info":[{"award-number":["ES\/P011055\/1"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009021","name":"Heart Research Australia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009021","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Large observational and Mendelian randomization (MR) studies have demonstrated a strong association between both elevated LDL cholesterol (LDL-c) and triglycerides (TG) with risk of aortic stenosis (AS), although randomized trials showed no benefit of statins for AS. It consequently remains uncertain whether lipid-lowering therapies have a role to prevent or treat AS. We used a drug-target MR approach to investigate the genetically predicted effect of lipid-lowering therapies on risk of AS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We collected summary statistics for LDL-c, TG, and AS from genome-wide association studies (GWAS) including 1\u00a0320\u00a0016, 1\u00a0253\u00a0277, and 412\u00a0181 European participants from the Global Lipids Genetics Consortium and FinnGen study, respectively. We identified genetic proxies for PCSK9 inhibitors, statins, bempedoic acid, and ezetimibe as single nucleotide polymorphisms in or within 200\u00a0kb of the target genes (PCSK9, HMGCR, ACLY, and NPC1L1, respectively), which were also significantly associated with LDL-c at P\u00a0&amp;lt;\u00a05\u00a0\u00d7\u00a010\u22128. We used a similar approach to identify genetic proxies for the TG-lowering agents fenofibrates, APOC3 inhibitors, and ANGPTL3 inhibitors using the target genes PPARA, APOC3, and ANGPTL3, respectively. Inverse variance-weighted was the primary analysis method. Sensitivity analyses included weighted median, weighted mode, and MR-Egger, followed by the outlier-exclusion approaches MR-PRESSO and Cook's distance. We also performed multivariable analyses to evaluate whether the predicted effect of PCSK9 inhibition may be mediated by lipoprotein(a). We performed replication and negative control analyses using GWAS of AS and height including 653\u00a0867 and 408\u00a0112 participants, respectively. Genetically proxied PCSK9 inhibition was significantly associated with reduced AS risk (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.52\u20130.72, P\u00a0&amp;lt;\u00a00.0001) on main, replication, and all sensitivity analyses. Genetically proxied ezetimibe (OR 0.49, 95% CI 0.31\u20130.78, P\u00a0=\u00a00.003), bempedoic acid (OR 0.0054, 95% CI 0.0002\u20130.12, P\u00a0=\u00a00.0009), and statins (OR 0.61, 95% CI 0.46\u20130.81, P\u00a0=\u00a00.0006) were similarly associated with reduced AS risk, although the latter were not significant on replication analyses. Amongst the TG-lowering agents, genetically proxied APOC3 inhibition was associated with reduced AS risk (OR 0.78, 95% CI 0.70\u20130.88, P\u00a0&amp;lt;\u00a00.0001), but fenofibrate (OR 0.64, 95% CI 0.09\u20134.53, P\u00a0=\u00a00.65) and ANGPTL3 inhibitors (OR 1.05, 95% CI 0.77\u20131.43, P\u00a0=\u00a00.74) were not.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Genetically proxied lipid-lowering therapies are significantly associated with reduced risk of AS. Early initiation and sustained administration of lipid-lowering therapies may prevent AS progression and warrants further research in the clinical trial setting.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ehjcvp\/pvae092","type":"journal-article","created":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T10:33:44Z","timestamp":1732876424000},"page":"136-142","source":"Crossref","is-referenced-by-count":12,"title":["Lipid-lowering therapies for aortic stenosis: a drug-target Mendelian randomization study"],"prefix":"10.1093","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4476-6051","authenticated-orcid":false,"given":"Jonathan L","family":"Ciofani","sequence":"first","affiliation":[{"name":"Sydney Medical School, The University of Sydney , Camperdown, NSW 2006 ,","place":["Australia"]},{"name":"Department of Cardiology, Royal North Shore Hospital , Reserve Road, St Leonards, NSW 2065 ,","place":["Australia"]},{"name":"Department of Epidemiology and 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of Public Health, Imperial College London , Exhibition Rd, South Kensington, London SW7 2AZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1505-2570","authenticated-orcid":false,"given":"Benjamin","family":"Woolf","sequence":"additional","affiliation":[{"name":"MRC Biostatistics Unit, University of Cambridge , Cambridge CB2 1TN ,","place":["UK"]},{"name":"MRC Integrative Epidemiology Unit, University of Bristol , Bristol BS8 1QU ,","place":["UK"]},{"name":"School of Psychological Science, University of Bristol , Bristol BS8 1QU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazem","family":"Rahimi","sequence":"additional","affiliation":[{"name":"Deep Medicine, Oxford Martin School, University of Oxford , Oxford OX1 2JD ,","place":["UK"]},{"name":"Nuffield Department of Women's and Reproductive Health, Medical Science Division, University of Oxford , Oxford OX1 2JD 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