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Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk
Xinmin S. Li, … , W.H. Wilson Tang, Stanley L. Hazen
Xinmin S. Li, … , W.H. Wilson Tang, Stanley L. Hazen
Published March 22, 2018
Citation Information: JCI Insight. 2018;3(6):e99096. https://doi.org/10.1172/jci.insight.99096.
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Research Article Cardiology Vascular biology

Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk

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Abstract

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.

Authors

Xinmin S. Li, Zeneng Wang, Tomas Cajka, Jennifer A. Buffa, Ina Nemet, Alex G. Hurd, Xiaodong Gu, Sarah M. Skye, Adam B. Roberts, Yuping Wu, Lin Li, Christopher J. Shahen, Matthew A. Wagner, Jaana A. Hartiala, Robert L. Kerby, Kymberleigh A. Romano, Yi Han, Slayman Obeid, Thomas F. Lüscher, Hooman Allayee, Federico E. Rey, Joseph A. DiDonato, Oliver Fiehn, W.H. Wilson Tang, Stanley L. Hazen

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Figure 1

Untargeted metabolomics studies discover candidate compound with m/z of 189.1598 is associated with CVD and is trimethyllysine.

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Untargeted metabolomics studies discover candidate compound with m/z of ...
(A) Forest plot indicating plasma metabolite of unknown structure with m/z of 189.1 is associated with risk for cardiovascular disease (CVD) according to relative peak area intensity ranked by tertiles among subjects (N = 99) in discovery cohort 1. (B) Forest plot indicating plasma metabolite of unknown structure with high-resolution m/z of 189.1598 is associated with the risk for incident CVD and mortality risks according to relative peak intensity from untargeted mass spectrometry analyses of subjects (N = 1,162; discovery cohort 2). MACE, major adverse cardiac events, including myocardial infarction, stroke, or death. The analyses were performed using R 3.4.1. (C) Collision-induced dissociation (CID) spectrum in positive-ion mode of the metabolite m/z of 189.1598 in plasma. (D) CID spectra in positive mode of synthetic trimethyllysine (TML) standard. (E) Demonstration of cochromatography of multiple unique parent→daughter ion transitions for plasma analyte m/z 189.1598 and synthetic d9-TML.

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