Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk
| Autor: | W.H. Wilson Tang, Stanley L. Hazen, Jaana Hartiala, Yuping Wu, Tomas Cajka, Thomas F. Lüscher, Sarah M. Skye, Adam B. Roberts, Jennifer A. Buffa, Kymberleigh A. Romano, Christopher J. Shahen, Hooman Allayee, Lin Li, Robert L. Kerby, Yi Han, Xiaodong Gu, Xinmin S. Li, Slayman Obeid, Oliver Fiehn, Matthew A. Wagner, Joseph A. DiDonato, Alex G Hurd, Zeneng Wang, Ina Nemet, Federico E. Rey |
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| Přispěvatelé: | University of Zurich |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Metabolite Trimethylamine 2700 General Medicine 030204 cardiovascular system & hematology Inbred C57BL Cardiovascular Choline 11459 Center for Molecular Cardiology Feces Mice chemistry.chemical_compound 0302 clinical medicine Nutrient Risk Factors General Medicine Middle Aged Cardiovascular disease 3. Good health Heart Disease Cholesterol Untargeted metabolomics Cardiovascular Diseases 10209 Clinic for Cardiology Female Research Article medicine.medical_specialty Cardiology 610 Medicine & health Methylamines 03 medical and health sciences Vascular Biology In vivo Carnitine Internal medicine medicine Animals Humans Metabolomics Nutrition Aged Animal Prevention Lysine Thrombosis Nutrients Atherosclerosis Gastrointestinal Microbiome Mice Inbred C57BL Disease Models Animal Good Health and Well Being 030104 developmental biology Endocrinology chemistry Disease Models Disease risk Genome-Wide Association Study |
| Zdroj: | JCI insight, vol 3, iss 6 |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.99096 |
| Popis: | Using an untargeted metabolomics approach in initial (N = 99 subjects) and replication cohorts (N = 1,162), we discovered and structurally identified a plasma metabolite associated with cardiovascular disease (CVD) risks, N6,N6,N6-trimethyl-L-lysine (trimethyllysine, TML). Stable-isotope-dilution tandem mass spectrometry analyses of an independent validation cohort (N = 2,140) confirmed TML levels are independently associated with incident (3-year) major adverse cardiovascular event risks (hazards ratio [HR], 2.4; 95% CI, 1.7-3.4) and incident (5-year) mortality risk (HR, 2.9; 95% CI, 2.0-4.2). Genome-wide association studies identified several suggestive loci for TML levels, but none reached genome-wide significance; and d9(trimethyl)-TML isotope tracer studies confirmed TML can serve as a nutrient precursor for gut microbiota-dependent generation of trimethylamine (TMA) and the atherogenic metabolite trimethylamine N-oxide (TMAO). Although TML was shown to be abundant in both plant- and animal-derived foods, mouse and human fecal cultures (omnivores and vegans) showed slow conversion of TML to TMA. Furthermore, unlike chronic dietary choline, TML supplementation in mice failed to elevate plasma TMAO or heighten thrombosis potential in vivo. Thus, TML is identified as a strong predictor of incident CVD risks in subjects and to serve as a dietary precursor for gut microbiota-dependent generation of TMAO; however, TML does not appear to be a major microbial source for TMAO generation in vivo. |
| Databáze: | OpenAIRE |
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