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In experimental models, higher blood TMAO levels enhance atherosclerotic cardiovascular disease (ASCVD). However in humans, most prior studies have evaluated high risk or secondary prevention populations, and no studies have investigated relationships in a diverse, multi-ethnic population. We evaluated 6,767 US adults free of ASCVD at baseline in the community-based Multi-Ethnic Study of Atherosclerosis (MESA), including 38% identifying as White; 28%, as Black; 22%, as Hispanic; and 12%, as Chinese adults. Plasma TMAO was measured serially at baseline and 5-years, and its time-varying association with incident ASCVD determined using Cox proportional hazards. Multivariate analyses adjusted for time-varying demographics, lifestyle factors, medical history, lipid measures, antibiotic use and dietary habits. During median 11.3 years follow-up, 852 ASCVD events occurred. After multivariate adjustment, TMAO associated with higher risk of ASCVD in a dose-dependent fashion, with hazard ratios across quintiles of 1.02, 1.17, 1.23, and 1.33 (95% CI 1.02, 1.74), respectively, compared to the lowest quintile (P-trend\u2009=\u20090.01). Risk appeared possibly larger among Hispanic and Chinese adults; and among individuals with lower baseline renal function; although these interactions did not achieve statistical significance. Plasma concentrations of TMAO associated with higher risk of incident ASCVD in this multi-ethnic US cohort, supporting a need to test dietary and pharmacologic interventions targeting the diet-microbiome axis for potential cardiovascular risk prevention in diverse populations.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-05903-3","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:50:18Z","timestamp":1751417418000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Trimethylamine-N-oxide (TMAO) and risk of incident cardiovascular events in the multi ethnic study of Atherosclerosis"],"prefix":"10.1038","volume":"15","author":[{"given":"Matthew J.","family":"Budoff","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcia C.","family":"de Oliveira Otto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinmin S.","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujin","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi T. 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Drs Hazen and Wang report being named as co-inventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Drs SL Hazen and Z Wang report having received royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab, a fully owned subsidiary of Quest Diagnostics, and Procter & Gamble. Dr. Hazen is a paid consultant for Zehna Therapeutics, and has received research funds from Zehna Therapeutics, Proctor & Gamble, Pfizer Inc., and Roche Diagnostics. Dr Psaty reported serving on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Dr Mozaffarian reported receiving personal fees from Acasti Pharma Inc and Barilla; serving on the scientific advisory board for Beren Therapeutics, Brightseed, Calibrate, Elysium Health, Filtricine Inc, Foodome, HumanCo, Instacart, January, Inc, Perfect Day Inc, and (ended) Day Two, Discern Dx, Season Health, and Tiny Organics; and receiving chapter royalties from UpToDate outside the submitted work. No other disclosures were reported.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosures"}}],"article-number":"23362"}}