{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T03:29:40Z","timestamp":1786764580622,"version":"build-2736575974"},"reference-count":37,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>\n                    Low\u2010dose aspirin is no longer routinely recommended for the primary prevention of cardiovascular disease in older adults due to a lack of net benefit over bleeding risk. We hypothesized that genetic subgroups may experience differential harm or benefit from aspirin therapy. To investigate this, we screened 572 polygenic scores (PGSs) for modification of aspirin's effect on major bleeding and major adverse cardiovascular events (MACE) in the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, placebo\u2010controlled trial of daily 100\u2009mg aspirin. Participants were aged \u226570\u2009years (\u226565\u2009years for US minorities) and free of cardiovascular disease, dementia, or physical disability at enrolment. Among participants with high\u2010quality genotyping data (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200913,571), PGS\u2013aspirin interactions were tested using Cox proportional hazards models with Bonferroni correction for multiple testing. During a median follow\u2010up of 4.6\u2009years, 414 major bleeding events and 464 MACE occurred. A triglyceride\u2010related PGS (PGS003144) significantly modified aspirin\u2010associated bleeding (interaction\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20095.9\u2009\u00d7\u200910\n                    <jats:sup>\u22125<\/jats:sup>\n                    ; Bonferroni\u2010adjusted\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.034). In the lowest quintile of the PGS distribution, aspirin increased major bleeding risk (HR 2.28; 95% CI: 1.45\u20133.58;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.00036), including separate bleeding subgroups gastrointestinal (HR 3.17; 95% CI: 1.48\u20136.80;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0029), and intracranial bleeding (HR 4.10; 95% CI: 1.54\u201311.0;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0049). In contrast, in the highest quintile, aspirin was associated with lower risk of bleeding (HR 0.62; 95% CI 0.38\u20130.97) and reduced MACE (HR 0.66; 95% CI 0.44\u20130.99). Baseline serum triglycerides showed similar effect modification. These hypothesis\u2010generating findings suggest triglyceride\u2010related genetic variation may identify individuals with differential responses to aspirin.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70446","type":"journal-article","created":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T03:26:04Z","timestamp":1786764364000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Triglyceride Polygenic Score Identifies Individuals Who May Respond Differently to Aspirin in Primary Prevention"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3515-0557","authenticated-orcid":false,"given":"Peter D.","family":"Fransquet","sequence":"first","affiliation":[{"name":"School of Public Health and Preventive Medicine Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0546-2779","authenticated-orcid":false,"given":"Chenglong","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine Monash University  Melbourne Victoria Australia"},{"name":"Victorian Heart Institute Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cammie","family":"Tran","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7894-2485","authenticated-orcid":false,"given":"Sultana Monira","family":"Hussain","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6303-8696","authenticated-orcid":false,"given":"Chad A.","family":"Bousman","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Physiology &amp; Pharmacology, and Psychiatry University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Menzies Institute for Medical Research University of Tasmania  Dynnyrne Tasmania Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Tonkin","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"McNeil","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0902-6798","authenticated-orcid":false,"given":"Paul","family":"Lacaze","sequence":"additional","affiliation":[{"name":"School of Public Health and Preventive Medicine Monash University  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"e_1_2_12_1_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1136\/bmj.324.7329.71","article-title":"Collaborative meta\u2010analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients","volume":"324","year":"2002","journal-title":"BMJ"},{"key":"e_1_2_12_2_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0160046","article-title":"Bleeding risk with long\u2010term low\u2010dose aspirin: a systematic review of observational studies","volume":"11","author":"Garc\u00eda Rodr\u00edguez L.A.","year":"2016","journal-title":"PLoS One"},{"key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1056\/NEJMoa1805819","article-title":"Effect of aspirin on cardiovascular events and bleeding in the healthy elderly","volume":"379","author":"McNeil J.J.","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"357","DOI":"10.7326\/M18-2808","article-title":"Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: a cohort study","volume":"170","author":"Selak V.","year":"2019","journal-title":"Ann. Intern. Med."},{"key":"e_1_2_12_5_1","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1056\/NEJMoa1804988","article-title":"Effects of aspirin for primary prevention in persons with diabetes mellitus","volume":"379","author":"Bowman L.","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"e_1_2_12_6_1","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/S0140-6736(18)31924-X","article-title":"Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double\u2010blind, placebo\u2010controlled trial","volume":"392","author":"Gaziano J.M.","year":"2018","journal-title":"The Lancet."},{"key":"e_1_2_12_7_1","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.jacc.2022.07.027","article-title":"Aspirin for primary prevention of cardiovascular events in relation to lipoprotein(a) genotypes","volume":"80","author":"Lacaze P.","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"e_1_2_12_8_1","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1038\/s41588-018-0222-9","article-title":"Genetics of blood lipids among ~300,000 multi\u2010ethnic participants of the million veteran program","volume":"50","author":"Klarin D.","year":"2018","journal-title":"Nat. Genet."},{"key":"e_1_2_12_9_1","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nature10659","article-title":"New gene functions in megakaryopoiesis and platelet formation","volume":"480","author":"Gieger C.","year":"2011","journal-title":"Nature"},{"key":"e_1_2_12_10_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ebiom.2024.105315","article-title":"Collagen IV deficiency causes hypertrophic remodeling and endothelium\u2010dependent hyperpolarization in small vessel disease with intracerebral hemorrhage","volume":"107","author":"McNeilly S.","year":"2024","journal-title":"EBioMedicine"},{"key":"e_1_2_12_11_1","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1002\/ana.26426","article-title":"Lipids, apolipoproteins, statins, and intracerebral hemorrhage: a Mendelian randomization study","volume":"92","author":"Yu Z.","year":"2022","journal-title":"Ann. Neurol."},{"key":"e_1_2_12_12_1","doi-asserted-by":"crossref","first-page":"428","DOI":"10.5694\/mja2.52278","article-title":"Genetic testing in cardiovascular disease","volume":"220","author":"Gray M.P.","year":"2024","journal-title":"Med. J. Aust."},{"key":"e_1_2_12_13_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1023\/A:1022066305399","article-title":"Aspirin resistance and genetic polymorphisms","volume":"14","author":"Cambria\u2010Kiely J.A.","year":"2002","journal-title":"J. Thromb. Thrombolysis"},{"key":"e_1_2_12_14_1","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1055\/s-0042-1758445","article-title":"Impact of pharmacogenetics on aspirin resistance: a systematic review","volume":"81","author":"Silva G.F.D.","year":"2023","journal-title":"Arq. Neuropsiquiatr."},{"key":"e_1_2_12_15_1","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1093\/gerona\/glw342","article-title":"Baseline characteristics of participants in the ASPREE (ASPirin in reducing events in the elderly) study","volume":"72","author":"McNeil J.J.","year":"2017","journal-title":"J.\u00a0Gerontol. A Biol. Sci. Med. Sci."},{"key":"e_1_2_12_16_1","doi-asserted-by":"crossref","DOI":"10.1002\/mpr.1608","article-title":"A tutorial on conducting genome\u2010wide association studies: quality control and statistical analysis","volume":"27","author":"Marees A.T.","year":"2018","journal-title":"Int. J.\u00a0Methods Psychiatr. 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Intern. Med."},{"key":"e_1_2_12_27_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/j.2040-4603.2018.tb00008.x","article-title":"Triglyceride metabolism in the liver","volume":"8","author":"Alves\u2010Bezerra M.","year":"2017","journal-title":"Compr. Physiol."},{"key":"e_1_2_12_28_1","first-page":"582","article-title":"Lipid profile and lipoprotein(a) testing","volume":"120","author":"Parhofer K.G.","year":"2023","journal-title":"Dtsch. Arztebl. 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Dis."},{"key":"e_1_2_12_34_1","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1111\/j.1538-7836.2007.02596.x","article-title":"High levels of low\u2010density lipoprotein cholesterol and triglycerides and suboptimal glycemic control predict diminished ex\u00a0vivo aspirin responsiveness in patients with type 2 diabetes1","volume":"5","author":"Hovens M.M.C.","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"e_1_2_12_35_1","first-page":"98","article-title":"Thrombosis in thrombocythemic Ph\u2010 myeloproliferations is associated with higher platelet count prior to the event: results of analyses of prothrombotic risk factors from a registry of patients treated with anagrelide","volume":"96","author":"Schwarz J.","year":"2016","journal-title":"Eur.\u00a0J.\u00a0Haematol."},{"issue":"1","key":"e_1_2_12_36_1","doi-asserted-by":"crossref","first-page":"S296","DOI":"10.1016\/j.ajog.2021.11.499","article-title":"Aspirin reduces triglycerides in both preeclamptic and non\u2010preeclamptic pregnancies","volume":"226","author":"Santillan D.A.","year":"2022","journal-title":"Am. J. Obstet. Gynecol."},{"key":"e_1_2_12_37_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.numecd.2020.10.014","article-title":"Lipid levels and the risk of hemorrhagic stroke: a dose\u2013response meta\u2010analysis","volume":"31","author":"Jin X.","year":"2021","journal-title":"Nutr. 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Dis."}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70446","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70446","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70446","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T03:26:10Z","timestamp":1786764370000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70446"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":37,"alternative-id":["10.1002\/cpt.70446"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70446","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]},"assertion":[{"value":"2026-03-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cpt.70446"}}