{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T21:13:58Z","timestamp":1789074838126,"version":"build-2803163510"},"reference-count":67,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Cardiovasc Res"],"DOI":"10.1038\/s44161-026-00865-9","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T09:02:43Z","timestamp":1788426163000},"page":"835-847","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic evidence supports the combined targeting of lipoprotein(a) and LDL cholesterol to reduce coronary artery disease risk"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8355-6103","authenticated-orcid":false,"given":"Shaoqi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3328-7185","authenticated-orcid":false,"given":"Yuzhong","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Sui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqiang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asifullah","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqing","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuli","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingfeng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoqi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9159-7310","authenticated-orcid":false,"given":"Fei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangli","family":"Mi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5577-5899","authenticated-orcid":false,"given":"Kelvin","family":"Supriami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Seo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjie","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajing","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0447-736X","authenticated-orcid":false,"given":"Jie","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenglong","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1135-9647","authenticated-orcid":false,"given":"Sarah","family":"Urbut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8630-5021","authenticated-orcid":false,"given":"Michael C.","family":"Honigberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8402-7435","authenticated-orcid":false,"given":"Pradeep","family":"Natarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JinPing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4849-6389","authenticated-orcid":false,"given":"Akl C.","family":"Fahed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3753-508X","authenticated-orcid":false,"given":"Minxian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"865_CR1","first-page":"e1082","volume":"139","author":"SM Grundy","year":"2018","unstructured":"Grundy, S. M. et al. 2018 AHA\/ACC\/AACVPR\/AAPA\/ABC\/ACPM\/ADA\/AGS\/APhA\/ASPC\/NLA\/PCNA Guideline on the Management of Blood Cholesterol. Circulation 139, e1082\u2013e1143 (2018).","journal-title":"Circulation"},{"key":"865_CR2","doi-asserted-by":"publisher","first-page":"1945","DOI":"10.1016\/j.jacc.2019.11.072","volume":"75","author":"D Preiss","year":"2020","unstructured":"Preiss, D., Tobert, J. A., Hovingh, G. K. & Reith, C. Lipid-modifying agents, from statins to PCSK9 inhibitors. J. Am. Coll. Cardiol. 75, 1945\u20131955 (2020).","journal-title":"J. Am. Coll. Cardiol."},{"key":"865_CR3","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1056\/NEJMra1806939","volume":"381","author":"ED Michos","year":"2019","unstructured":"Michos, E. D., McEvoy, J. W. & Blumenthal, R. S. Lipid management for the prevention of atherosclerotic cardiovascular disease. N. Engl. J. Med. 381, 1557\u20131567 (2019).","journal-title":"N. Engl. J. Med."},{"key":"865_CR4","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1056\/NEJMoa1615664","volume":"376","author":"MS Sabatine","year":"2017","unstructured":"Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713\u20131722 (2017).","journal-title":"N. Engl. J. Med."},{"key":"865_CR5","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1056\/NEJMoa1801174","volume":"379","author":"GG Schwartz","year":"2018","unstructured":"Schwartz, G. G. et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N. Engl. J. Med. 379, 2097\u20132107 (2018).","journal-title":"N. Engl. J. Med."},{"key":"865_CR6","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1161\/CIRCULATIONAHA.124.069210","volume":"151","author":"A Greco","year":"2025","unstructured":"Greco, A. et al. Lipoprotein(a) as a pharmacological target: premises, promises, and prospects. Circulation 151, 400\u2013415 (2025).","journal-title":"Circulation"},{"key":"865_CR7","doi-asserted-by":"publisher","first-page":"e48","DOI":"10.1161\/ATV.0000000000000147","volume":"42","author":"G Reyes-Soffer","year":"2022","unstructured":"Reyes-Soffer, G. et al. Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American Heart Association. Arterioscler. Thromb. Vasc. Biol. 42, e48\u2013e60 (2022).","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"865_CR8","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1001\/jamacardio.2022.0987","volume":"7","author":"F Duarte Lau","year":"2022","unstructured":"Duarte Lau, F. & Giugliano, R. P. Lipoprotein(a) and its significance in cardiovascular disease: a review. JAMA Cardiol. 7, 760\u2013769 (2022).","journal-title":"JAMA Cardiol."},{"key":"865_CR9","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1001\/jamacardio.2025.1603","volume":"108","author":"HS Bhatia","year":"2025","unstructured":"Bhatia, H. S. et al. AHA PREVENT equations and lipoprotein(a) for cardiovascular disease risk: insights from MESA and the UK biobank. JAMA Cardiol 108, 810\u2013818 https:\/\/doi.org\/10.1001\/jamacardio.2025.1603 (2025).","journal-title":"JAMA Cardiol"},{"key":"865_CR10","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1161\/CIRCULATIONAHA.113.004406","volume":"129","author":"AV Khera","year":"2014","unstructured":"Khera, A. V. et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the Jupiter trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). Circulation 129, 635\u2013642 (2014).","journal-title":"Circulation"},{"key":"865_CR11","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1161\/CIRCULATIONAHA.124.069556","volume":"151","author":"HS Bhatia","year":"2025","unstructured":"Bhatia, H. S. et al. Independence of lipoprotein(a) and low-density lipoprotein cholesterol\u2013mediated cardiovascular risk: a participant-level meta-analysis. Circulation 151, 312\u2013321 (2025).","journal-title":"Circulation"},{"key":"865_CR12","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1161\/CIRCULATIONAHA.118.037184","volume":"139","author":"ML O\u2019Donoghue","year":"2019","unstructured":"O\u2019Donoghue, M. L. et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 139, 1483\u20131492 (2019).","journal-title":"Circulation"},{"key":"865_CR13","doi-asserted-by":"publisher","first-page":"1855","DOI":"10.1056\/NEJMoa2211023","volume":"387","author":"ML O\u2019Donoghue","year":"2022","unstructured":"O\u2019Donoghue, M. L. et al. Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. N. Engl. J. Med. 387, 1855\u20131864 (2022).","journal-title":"N. Engl. J. Med."},{"key":"865_CR14","doi-asserted-by":"publisher","first-page":"1673","DOI":"10.1056\/NEJMoa2415818","volume":"392","author":"SE Nissen","year":"2025","unstructured":"Nissen, S. E. et al. Lepodisiran\u2014a long-duration small interfering RNA targeting lipoprotein(a). N. Engl. J. Med. 392, 1673\u20131683 (2025).","journal-title":"N. Engl. J. Med."},{"key":"865_CR15","doi-asserted-by":"publisher","first-page":"1992","DOI":"10.1001\/jama.2024.21957","volume":"332","author":"SE Nissen","year":"2024","unstructured":"Nissen, S. E. et al. Zerlasiran\u2014a small-interfering RNA targeting lipoprotein(a): a phase 2 randomized clinical trial. JAMA 332, 1992\u20132002 (2024).","journal-title":"JAMA"},{"key":"865_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ahj.2025.03.019","volume":"287","author":"L Cho","year":"2025","unstructured":"Cho, L. et al. Design and rationale of lp(a)HORIZON trial: assessing the effect of lipoprotein(a) lowering with pelacarsen on major cardiovascular events in patients with CVD and elevated Lp(a). Am. Heart J. 287, 1\u20139 (2025).","journal-title":"Am. Heart J."},{"key":"865_CR17","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1016\/j.jacc.2023.02.033","volume":"81","author":"WA Malick","year":"2023","unstructured":"Malick, W. A., Goonewardena, S. N., Koenig, W. & Rosenson, R. S. Clinical trial design for lipoprotein(a)-lowering therapies. J. Am. Coll. Cardiol. 81, 1633\u20131645 (2023).","journal-title":"J. Am. Coll. Cardiol."},{"key":"865_CR18","doi-asserted-by":"publisher","first-page":"e8","DOI":"10.1016\/j.atherosclerosis.2019.06.021","volume":"287","author":"J Katzmann","year":"2019","unstructured":"Katzmann, J., Laufs, U. & Ference, B. A. A mendelian randomization analysis of lipoprotein(a) lowering and cardiovascular risk stratified by ldl cholesterol, gender, and antiplatelet therapy: implications for clinical outcome trials. Atherosclerosis 287, e8 (2019).","journal-title":"Atherosclerosis"},{"key":"865_CR19","doi-asserted-by":"publisher","first-page":"dyaf020","DOI":"10.1093\/ije\/dyaf020","volume":"54","author":"L Wang","year":"2025","unstructured":"Wang, L. et al. Factorial mendelian randomization of lipoprotein (a) lowering, low-density lipoprotein cholesterol lowering, and lifestyle improvements: joint associations with cardiovascular risk. Int. J. Epidemiol. 54, dyaf020 (2025).","journal-title":"Int. J. Epidemiol."},{"key":"865_CR20","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1001\/jamacardio.2018.1470","volume":"3","author":"S Burgess","year":"2018","unstructured":"Burgess, S. et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a mendelian randomization analysis. JAMA Cardiol. 3, 619\u2013627 (2018).","journal-title":"JAMA Cardiol."},{"key":"865_CR21","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1093\/cvr\/cvab060","volume":"117","author":"M Trinder","year":"2021","unstructured":"Trinder, M., Zekavat, S. M., Uddin, M. M., Pampana, A. & Natarajan, P. Apolipoprotein B is an insufficient explanation for the risk of coronary disease associated with lipoprotein(a). Cardiovasc. Res. 117, 1245\u20131247 (2021).","journal-title":"Cardiovasc. Res."},{"key":"865_CR22","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/s11883-024-01195-6","volume":"26","author":"R Abou-Karam","year":"2024","unstructured":"Abou-Karam, R., Cheng, F., Gady, S. & Fahed, A. C. The role of genetics in advancing cardiometabolic drug development. Curr. Atheroscler. Rep. 26, 153\u2013162 (2024).","journal-title":"Curr. Atheroscler. Rep."},{"key":"865_CR23","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1001\/jamacardio.2025.0195","volume":"10","author":"W Wang","year":"2025","unstructured":"Wang, W. et al. Joint associations of APOC3 and LDL-C\u2013lowering variants with the risk of coronary heart disease. JAMA Cardiol. 10, 463\u2013472 (2025).","journal-title":"JAMA Cardiol."},{"key":"865_CR24","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1056\/NEJMoa1612790","volume":"377","author":"FE Dewey","year":"2017","unstructured":"Dewey, F. E. et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N. Engl. J. Med. 377, 211\u2013221 (2017).","journal-title":"N. Engl. J. Med."},{"key":"865_CR25","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1056\/NEJMoa1308027","volume":"371","author":"AB J\u00f8rgensen","year":"2014","unstructured":"J\u00f8rgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G. & Tybj\u00e6rg-Hansen, A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371, 32\u201341 (2014).","journal-title":"N. Engl. J. Med."},{"key":"865_CR26","doi-asserted-by":"publisher","first-page":"2075","DOI":"10.1001\/jama.2023.21835","volume":"330","author":"SE Nissen","year":"2023","unstructured":"Nissen, S. E. et al. Lepodisiran, an extended-duration short interfering RNA targeting lipoprotein(a): a randomized dose-ascending clinical trial. JAMA 330, 2075\u20132083 (2023).","journal-title":"JAMA"},{"key":"865_CR27","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.1038\/s41588-024-01930-4","volume":"56","author":"SM Gaynor","year":"2024","unstructured":"Gaynor, S. M. et al. Yield of genetic association signals from genomes, exomes and imputation in the UK biobank. Nat. Genet. 56, 2345\u20132351 (2024).","journal-title":"Nat. Genet."},{"key":"865_CR28","doi-asserted-by":"publisher","first-page":"2091","DOI":"10.1161\/CIRCULATIONAHA.116.024436","volume":"135","author":"P Natarajan","year":"2017","unstructured":"Natarajan, P. et al. Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting. Circulation 135, 2091\u20132101 (2017).","journal-title":"Circulation"},{"key":"865_CR29","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1093\/ehjcvp\/pvae085","volume":"11","author":"C Yu","year":"2025","unstructured":"Yu, C. et al. Polygenic risk, aspirin, and primary prevention of coronary artery disease. Eur. Heart J. Cardiovasc. Pharmacother. 11, 84\u201391 (2025).","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"865_CR30","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","volume":"50","author":"M Verbanck","year":"2018","unstructured":"Verbanck, M., Chen, C.-Y., Neale, B. & Do, R. Detection of widespread horizontal pleiotropy in causal relationships inferred from mendelian randomization between complex traits and diseases. Nat. Genet. 50, 693\u2013698 (2018).","journal-title":"Nat. Genet."},{"key":"865_CR31","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","volume":"44","author":"J Bowden","year":"2015","unstructured":"Bowden, J., Davey Smith, G. & Burgess, S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44, 512\u2013525 (2015).","journal-title":"Int. J. Epidemiol."},{"key":"865_CR32","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1214\/19-AOS1866","volume":"48","author":"Q Zhao","year":"2020","unstructured":"Zhao, Q., Wang, J., Hemani, G., Bowden, J. & Small, D. S. Statistical inference in two-sample summary-data mendelian randomization using robust adjusted profile score. Ann. Stat. 48, 1742\u20131769 (2020).","journal-title":"Ann. Stat."},{"key":"865_CR33","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1038\/s41586-021-04064-3","volume":"600","author":"SE Graham","year":"2021","unstructured":"Graham, S. E. et al. The power of genetic diversity in genome-wide association studies of lipids. Nature 600, 675\u2013679 (2021).","journal-title":"Nature"},{"key":"865_CR34","volume":"4","author":"M Urbut Sarah","year":"2025","unstructured":"Urbut Sarah, M. et al. Genetics of cholesterol and coronary disease risk across six global ancestries. NEJM Evidence 4, EVIDoa2500105 (2025).","journal-title":"NEJM Evidence"},{"key":"865_CR35","doi-asserted-by":"publisher","first-page":"2144","DOI":"10.1056\/NEJMoa1604304","volume":"375","author":"BA Ference","year":"2016","unstructured":"Ference, B. A. et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N. Engl. J. Med. 375, 2144\u20132153 (2016).","journal-title":"N. Engl. J. Med."},{"key":"865_CR36","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1001\/jamacardio.2024.5072","volume":"10","author":"A Ravi","year":"2025","unstructured":"Ravi, A. et al. Genetic predisposition to low-density lipoprotein cholesterol and incident type 2 diabetes. JAMA Cardiol. 10, 379\u2013383 (2025).","journal-title":"JAMA Cardiol."},{"key":"865_CR37","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.1126\/science.abg8289","volume":"373","author":"RE Mukamel","year":"2021","unstructured":"Mukamel, R. E. et al. Protein-coding repeat polymorphisms strongly shape diverse human phenotypes. Science 373, 1499\u20131505 (2021).","journal-title":"Science"},{"key":"865_CR38","doi-asserted-by":"publisher","first-page":"e003182","DOI":"10.1161\/CIRCGEN.120.003182","volume":"14","author":"JS Dron","year":"2021","unstructured":"Dron, J. S. et al. Genetic predictor to identify individuals with high lipoprotein(a) concentrations. Circ. Genomic Precis. Med. 14, e003182 (2021).","journal-title":"Circ. Genomic Precis. Med."},{"key":"865_CR39","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1016\/j.jacc.2022.07.027","volume":"80","author":"P Lacaze","year":"2022","unstructured":"Lacaze, P. et al. Aspirin for primary prevention of cardiovascular events in relation to lipoprotein(a) genotypes. J. Am. Coll. Cardiol. 80, 1287\u20131298 (2022).","journal-title":"J. Am. Coll. Cardiol."},{"key":"865_CR40","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/clpt.2012.58","volume":"92","author":"B Zambrowicz","year":"2012","unstructured":"Zambrowicz, B. et al. LX4211, a dual SGLT1\/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin. Pharmacol. Ther. 92, 158\u2013169 (2012).","journal-title":"Clin. Pharmacol. Ther."},{"key":"865_CR41","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1161\/CIRCULATIONAHA.116.020838","volume":"134","author":"FM Van Der Valk","year":"2016","unstructured":"Van Der Valk, F. M. et al. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation 134, 611\u2013624 (2016).","journal-title":"Circulation"},{"key":"865_CR42","doi-asserted-by":"publisher","first-page":"2262","DOI":"10.1093\/eurheartj\/ehaa171","volume":"41","author":"LCA Stiekema","year":"2020","unstructured":"Stiekema, L. C. A. et al. Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a). Eur. Heart J. 41, 2262\u20132271 (2020).","journal-title":"Eur. Heart J."},{"key":"865_CR43","doi-asserted-by":"publisher","first-page":"100820","DOI":"10.1016\/j.jlr.2025.100820","volume":"66","author":"RS Rosenson","year":"2025","unstructured":"Rosenson, R. S. et al. Lipoprotein (a) integrates monocyte-mediated thrombosis and inflammation in atherosclerotic cardiovascular disease. J. Lipid Res. 66, 100820 (2025).","journal-title":"J. Lipid Res."},{"key":"865_CR44","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1161\/CIRCULATIONAHA.124.070632","volume":"151","author":"A Sittichokkananon","year":"2025","unstructured":"Sittichokkananon, A., Garfield, V. & Chiesa, S. T. Genetic and lifestyle risks for coronary artery disease and long-term risk of incident dementia subtypes. Circulation 151, 1235\u20131247 (2025).","journal-title":"Circulation"},{"key":"865_CR45","doi-asserted-by":"publisher","first-page":"2631","DOI":"10.1016\/j.jacc.2012.09.017","volume":"60","author":"BA Ference","year":"2012","unstructured":"Ference, B. A. et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease. J. Am. Coll. Cardiol. 60, 2631\u20132639 (2012).","journal-title":"J. Am. Coll. Cardiol."},{"key":"865_CR46","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","volume":"562","author":"C Bycroft","year":"2018","unstructured":"Bycroft, C. et al. The UK biobank resource with deep phenotyping and genomic data. Nature 562, 203\u2013209 (2018).","journal-title":"Nature"},{"key":"865_CR47","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1093\/ije\/dym276","volume":"37","author":"P Elliott","year":"2008","unstructured":"Elliott, P., Peakman, T. C. & on behalf of UK Biobank. The UK Biobank sample handling and storage protocol for the collection, processing and archiving of human blood and urine. Int. J. Epidemiol. 37, 234\u2013244 (2008).","journal-title":"Int. J. Epidemiol."},{"key":"865_CR48","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1038\/s41591-023-02429-x","volume":"29","author":"AP Patel","year":"2023","unstructured":"Patel, A. P. et al. A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease. Nat. Med. 29, 1793\u20131803 (2023).","journal-title":"Nat. Med."},{"key":"865_CR49","doi-asserted-by":"publisher","unstructured":"Koyama, S. et al. Decoding genetics, ancestry, and geospatial context for precision health. Preprint at medRxiv https:\/\/doi.org\/10.1101\/2023.10.24.23297096 (2023).","DOI":"10.1101\/2023.10.24.23297096"},{"key":"865_CR50","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.3390\/jpm12081323","volume":"12","author":"NT Boutin","year":"2022","unstructured":"Boutin, N. T. et al. The evolution of a large biobank at Mass General Brigham. J. Pers. Med. 12, 1323 (2022).","journal-title":"J. Pers. Med."},{"key":"865_CR51","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1161\/STROKEAHA.121.037388","volume":"53","author":"R Bhattacharya","year":"2022","unstructured":"Bhattacharya, R. et al. Clonal hematopoiesis is associated with higher risk of stroke. Stroke 53, 788\u2013797 (2022).","journal-title":"Stroke"},{"key":"865_CR52","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1038\/ng.3656","volume":"48","author":"S Das","year":"2016","unstructured":"Das, S. et al. Next-generation genotype imputation service and methods. Nat. Genet. 48, 1284\u20131287 (2016).","journal-title":"Nat. Genet."},{"key":"865_CR53","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","volume":"17","author":"W McLaren","year":"2016","unstructured":"McLaren, W. et al. The ensembl variant effect predictor. Genome Biol 17, 122\u2013136 (2016).","journal-title":"Genome Biol"},{"key":"865_CR54","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434\u2013443 (2020).","journal-title":"Nature"},{"key":"865_CR55","doi-asserted-by":"publisher","first-page":"5424","DOI":"10.1093\/bioinformatics\/btaa1029","volume":"36","author":"F Priv\u00e9","year":"2021","unstructured":"Priv\u00e9, F., Arbel, J. & Vilhj\u00e1lmsson, B. J. LDpred2: better, faster, stronger. Bioinformatics 36, 5424\u20135431 (2021).","journal-title":"Bioinformatics"},{"key":"865_CR56","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","volume":"526","author":"The 1000 Genomes Project Consortium","year":"2015","unstructured":"The 1000 Genomes Project Consortium A global reference for human genetic variation. Nature 526, 68\u201374 (2015).","journal-title":"Nature"},{"key":"865_CR57","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","volume":"613","author":"MI Kurki","year":"2023","unstructured":"Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508\u2013518 (2023).","journal-title":"Nature"},{"key":"865_CR58","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1038\/s41586-023-06563-x","volume":"622","author":"GH Eldjarn","year":"2023","unstructured":"Eldjarn, G. H. et al. Large-scale plasma proteomics comparisons through genetics and disease associations. Nature 622, 348\u2013358 (2023).","journal-title":"Nature"},{"key":"865_CR59","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","volume":"81","author":"S Purcell","year":"2007","unstructured":"Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559\u2013575 (2007).","journal-title":"Am. J. Hum. Genet."},{"key":"865_CR60","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/s41586-023-06592-6","volume":"622","author":"BB Sun","year":"2023","unstructured":"Sun, B. B. et al. Plasma proteomic associations with genetics and health in the UK Biobank. Nature 622, 329\u2013338 (2023).","journal-title":"Nature"},{"key":"865_CR61","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11122","volume":"7","author":"J Kettunen","year":"2016","unstructured":"Kettunen, J. et al. Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA. Nat. Commun. 7, 11122 (2016).","journal-title":"Nat. Commun."},{"key":"865_CR62","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.1038\/s41588-022-01233-6","volume":"54","author":"KG Aragam","year":"2022","unstructured":"Aragam, K. G. et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat. Genet. 54, 1803\u20131815 (2022).","journal-title":"Nat. Genet."},{"key":"865_CR63","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/gepi.21758","volume":"37","author":"S Burgess","year":"2013","unstructured":"Burgess, S., Butterworth, A. & Thompson, S. G. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet. Epidemiol. 37, 658\u2013665 (2013).","journal-title":"Genet. Epidemiol."},{"key":"865_CR64","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gepi.21965","volume":"40","author":"J Bowden","year":"2016","unstructured":"Bowden, J., Davey Smith, G., Haycock, P. C. & Burgess, S. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 40, 304\u2013314 (2016).","journal-title":"Genet. Epidemiol."},{"key":"865_CR65","doi-asserted-by":"crossref","unstructured":"Schwarzer, G., Carpenter, J. R. & R\u00fccker, G. Meta-Analysis with R (Springer, 2015).","DOI":"10.1007\/978-3-319-21416-0"},{"key":"865_CR66","doi-asserted-by":"publisher","first-page":"e34408","DOI":"10.7554\/eLife.34408","volume":"7","author":"G Hemani","year":"2018","unstructured":"Hemani, G. et al. The MR-base platform supports systematic causal inference across the human phenome. eLife 7, e34408 (2018).","journal-title":"eLife"},{"key":"865_CR67","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/s41592-019-0686-2","volume":"17","author":"P Virtanen","year":"2020","unstructured":"Virtanen, P. et al. SciPy 1.0: fundamental algorithms for scientific computing in python. Nat. Methods 17, 261\u2013272 (2020).","journal-title":"Nat. Methods"}],"container-title":["Nature Cardiovascular Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s44161-026-00865-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s44161-026-00865-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s44161-026-00865-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T21:02:26Z","timestamp":1789074146000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s44161-026-00865-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":67,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["865"],"URL":"https:\/\/doi.org\/10.1038\/s44161-026-00865-9","relation":{},"ISSN":["2731-0590"],"issn-type":[{"value":"2731-0590","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]},"assertion":[{"value":"1 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Y.S. reports serving as a consultant from Arboretum Lifesciences. P.N. has received research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech\/Roche and Novartis; personal fees from AiRNA, Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Bristol Myers Squibb, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Capital, Foresite Labs, Genentech\/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, Novo Nordisk, TenSixteen Bio and Tourmaline Bio; equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. M.C.H. has received consulting fees from Comanche Biopharma; site principal investigator work for Novartis; and research support from Genentech. A.C.F. reports being co-founder of Goodpath and Avigena, serving as scientific advisor to MyOme, Arboretum Health, HeartFlow and Aditum Bio, and receiving sponsored research awards from Foresite, Sarepta Therapeutics and Allelica. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}