Jae Jeong Yang1, Xiao-Ou Shu1, David M Herrington2, Steven C Moore3, Katie A Meyer4, Jennifer Ose5,6, Cristina Menni7, Nicholette D Palmer8, Heather Eliassen9, Sei Harada10, Ioanna Tzoulaki11,12,13,14, Huilian Zhu15, Demetrius Albanes3, Thomas J Wang16,17, Wei Zheng1, Hui Cai1, Cornelia M Ulrich5,6, Marta Guasch-Ferré9, Ibrahim Karaman11,12,13, Myriam Fornage18, Qiuyin Cai1, Charles E Matthews3, Lynne E Wagenknecht19, Paul Elliott11,12,13, Robert E Gerszten20,21, Danxia Yu1. 1. Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 2. Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA. 3. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. 4. Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA. 5. Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA. 6. Huntsman Cancer Institute, Salt Lake City, UT, USA. 7. Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom. 8. Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA. 9. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 10. Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan. 11. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom. 12. MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom. 13. Dementia Research Institute, Imperial College London, London, United Kingdom. 14. Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. 15. Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China. 16. Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. 17. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA. 18. Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA. 19. Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA. 20. Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. 21. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Abstract
BACKGROUND: Trimethylamine N-oxide (TMAO), a diet-derived, gut microbial-host cometabolite, has been linked to cardiometabolic diseases. However, the relations remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities. OBJECTIVES: To examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the United States, Europe, and Asia. METHODS: Included were 32,166 adults (16,269 white, 13,293 Asian, 1247 Hispanic/Latino, 1236 black, and 121 others) without cardiovascular disease, cancer, chronic kidney disease, or inflammatory bowel disease. Linear regression coefficients (β) were computed for standardized TMAO with harmonized variables. Study-specific results were combined by random-effects meta-analysis. A false discovery rate <0.10 was considered significant. RESULTS: After adjustment for potential confounders, circulating TMAO was associated with intakes of animal protein and saturated fat (β = 0.124 and 0.058, respectively, for a 5% energy increase) and with shellfish, total fish, eggs, and red meat (β = 0.370, 0.151, 0.081, and 0.056, respectively, for a 1 serving/d increase). Plant protein and nuts showed inverse associations (β = -0.126 for a 5% energy increase from plant protein and -0.123 for a 1 serving/d increase of nuts). Although the animal protein-TMAO association was consistent across populations, fish and shellfish associations were stronger in Asians (β = 0.285 and 0.578), and egg and red meat associations were more prominent in Americans (β = 0.153 and 0.093). Besides, circulating TMAO was positively associated with creatinine (β = 0.131 SD increase in log-TMAO), homocysteine (β = 0.065), insulin (β = 0.048), glycated hemoglobin (β = 0.048), and glucose (β = 0.023), whereas it was inversely associated with HDL cholesterol (β = -0.047) and blood pressure (β = -0.030). Each TMAO-biomarker association remained significant after further adjusting for creatinine and was robust in subgroup/sensitivity analyses. CONCLUSIONS: In an international, consortium-based study, animal protein was consistently associated with increased circulating TMAO, whereas TMAO associations with fish, shellfish, eggs, and red meat varied among populations. The adverse associations of TMAO with certain cardiometabolic biomarkers, independent of renal function, warrant further investigation.
BACKGROUND: Trimethylamine N-oxide (TMAO), a diet-derived, gut microbial-host cometabolite, has been linked to cardiometabolic diseases. However, the relations remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities. OBJECTIVES: To examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the United States, Europe, and Asia. METHODS: Included were 32,166 adults (16,269 white, 13,293 Asian, 1247 Hispanic/Latino, 1236 black, and 121 others) without cardiovascular disease, cancer, chronic kidney disease, or inflammatory bowel disease. Linear regression coefficients (β) were computed for standardized TMAO with harmonized variables. Study-specific results were combined by random-effects meta-analysis. A false discovery rate <0.10 was considered significant. RESULTS: After adjustment for potential confounders, circulating TMAO was associated with intakes of animal protein and saturated fat (β = 0.124 and 0.058, respectively, for a 5% energy increase) and with shellfish, total fish, eggs, and red meat (β = 0.370, 0.151, 0.081, and 0.056, respectively, for a 1 serving/d increase). Plant protein and nuts showed inverse associations (β = -0.126 for a 5% energy increase from plant protein and -0.123 for a 1 serving/d increase of nuts). Although the animal protein-TMAO association was consistent across populations, fish and shellfish associations were stronger in Asians (β = 0.285 and 0.578), and egg and red meat associations were more prominent in Americans (β = 0.153 and 0.093). Besides, circulating TMAO was positively associated with creatinine (β = 0.131 SD increase in log-TMAO), homocysteine (β = 0.065), insulin (β = 0.048), glycated hemoglobin (β = 0.048), and glucose (β = 0.023), whereas it was inversely associated with HDL cholesterol (β = -0.047) and blood pressure (β = -0.030). Each TMAO-biomarker association remained significant after further adjusting for creatinine and was robust in subgroup/sensitivity analyses. CONCLUSIONS: In an international, consortium-based study, animal protein was consistently associated with increased circulating TMAO, whereas TMAO associations with fish, shellfish, eggs, and red meat varied among populations. The adverse associations of TMAO with certain cardiometabolic biomarkers, independent of renal function, warrant further investigation.
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