{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:51:59Z","timestamp":1792803119044,"version":"4.5.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T00:00:00Z","timestamp":1741564800000},"content-version":"vor","delay-in-days":22,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"publisher","award":["82204019"],"award-info":[{"award-number":["82204019"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"American Heart Association Postdoctoral Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>High levels of lipoprotein(a) [Lp(a)] have been associated with an increased risk of cardiovascular disease (CVD); however, the effects of Lp(a)-lowering therapy in combination with low-density lipoprotein cholesterol (LDL-C)-lowering treatment or lifestyle improvements on CVD risk remain unexplored.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a factorial Mendelian randomization study among 385\u00a0917 participants in the UK Biobank. Separate genetic scores were constructed to proxy the effects of Lp(a) lowering, LDL-C lowering through different targets [HMG-CoA reductase, NPC1-like intracellular cholesterol transporter 1, proprotein convertase subtilisin\/kexin Type 9, and low-density lipoprotein receptor (LDLR)], as well as improvements in body mass index (BMI), systolic blood pressure (SBP), and lifestyle factors (cigarette smoking, alcohol consumption, and physical activity).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Genetically predicted lower Lp(a) levels were associated with a decreased risk of CVD and CVD-specific mortality. Per 50-mg\/dl, the hazard ratio ranged from 0.73 [95% confidence interval (CI): 0.73, 0.73] for peripheral artery disease (PAD) to 0.95 (95% CI: 0.92, 0.99) for venous thromboembolism. In factorial analyses exploring combined exposure to low-level Lp(a) and low-level LDL-C, there was no consistent evidence for departure from an additive model for any outcome (Pinteraction &amp;gt; .05), with the exception of the analysis using the LDLR score and PAD (Pinteraction = .006). In factorial analyses exploring combination therapies integrating Lp(a) lowering with interventions on BMI, SBP, and lifestyle factors, there was no evidence for departure from an additive model in any analysis (Pinteraction &amp;gt; .05).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our study suggests that Lp(a) lowering will have a similar magnitude for reducing cardiovascular events whether it is considered alone, or in conjunction with LDL-C reduction or lifestyle improvements.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ije\/dyaf020","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T22:27:51Z","timestamp":1741645671000},"source":"Crossref","is-referenced-by-count":11,"title":["Factorial Mendelian randomization of lipoprotein (a) lowering, low-density lipoprotein cholesterol lowering, and lifestyle improvements: joint associations with cardiovascular risk"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9797-0753","authenticated-orcid":false,"given":"Lijuan","family":"Wang","sequence":"first","affiliation":[{"name":"The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine , Hangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine , Hangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0046-6663","authenticated-orcid":false,"given":"Jing","family":"Sun","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine , Hangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhui","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine , Hangzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazhou","family":"He","sequence":"additional","affiliation":[{"name":"Department of Oncology, West China School of Public Health and West China Fourth Hospital, Sichuan University , Chengdu,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7312-7078","authenticated-orcid":false,"given":"Dipender","family":"Gill","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London , London,","place":["United Kingdom"]},{"name":"Sequoia Genetics , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5365-8760","authenticated-orcid":false,"given":"Stephen","family":"Burgess","sequence":"additional","affiliation":[{"name":"MRC Biostatistics Unit, University of Cambridge , Cambridge,","place":["United Kingdom"]},{"name":"Department of Public Health and Primary Care, University of Cambridge , Cambridge,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0118-0341","authenticated-orcid":false,"given":"Susanna C","family":"Larsson","sequence":"additional","affiliation":[{"name":"Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institute , Stockholm,","place":["Sweden"]},{"name":"Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University , Uppsala,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5055-5627","authenticated-orcid":false,"given":"Shuai","family":"Yuan","sequence":"additional","affiliation":[{"name":"Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institute , Stockholm,","place":["Sweden"]},{"name":"Department of Surgery, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA,","place":["United States"]},{"name":"Corporal Michael J. 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