Evidence map›Paper›PMID 29563342›Full record

ArticleJCI insight2018

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

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 and 15 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in JCI insight, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
92citing papers in PubMed, 3 pooled it
7.4field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

92 citing papers in PubMed, 3 syntheses or guidelines pooled it, 163 citations in OpenAlex.

  1. Pooled it
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  6. Review
  7. Gut microbes · 2026
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  19. Analysis types and quantification methods applied in UHPLC-MS metabolomics research: a tutorial.Metabolomics : Official journal of the Metabolomic Society · 2024
    Review
  20. Review

32 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

25 authors at 9 institutions in 4 countries.

Xinmin S LiDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Zeneng WangDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Tomas CajkaDepartment of Molecular and Cellular Biology and Genome Center, University of California Davis, Davis, California, USA.
Jennifer A BuffaDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Ina NemetDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Alex G HurdDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Xiaodong GuDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Sarah M SkyeDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Adam B RobertsDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Yuping WuDepartment of Mathematics, Cleveland State University, Cleveland, Ohio, USA.
Lin LiDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Christopher J ShahenDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Matthew A WagnerDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Jaana A HartialaDepartments of Preventive Medicine and Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.
Robert L KerbyDepartment of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Kymberleigh A RomanoDepartment of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Yi HanDepartments of Preventive Medicine and Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.
Slayman ObeidUniversity Heart Center, Department of Cardiology, University Hospital Zurich, Switzerland.
Thomas F LüscherUniversity Heart Center, Department of Cardiology, University Hospital Zurich, Switzerland.
Hooman AllayeeDepartments of Preventive Medicine and Biochemistry and Molecular Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.
Federico E ReyDepartment of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Joseph A DiDonatoDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Oliver FiehnDepartment of Molecular and Cellular Biology and Genome Center, University of California Davis, Davis, California, USA.
W H Wilson TangDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Stanley L HazenDepartment of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Cleveland Clinic Lerner College of Medicine · USUniversity of Southern California · USUniversity of Wisconsin–Madison · USCleveland Clinic · USCleveland State University · USHarefield Hospital · GBKing Abdulaziz University · SAUniversity Hospital of Zurich · CHUniversity of California, Davis · US

Funding

Structural Determinants Of Ceruloplasmin Inflammatory ActivityP01HL076491 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI PLOW, EDWARD FRANKLIN · 2004 to 2019
$27.3M
Gut Flora Metabolism of Dietary Phosphatidylcholine and CVDR01HL103866 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI HAZEN, STANLEY L · 2010 to 2023
$10.8M
Functional Cardio-MetabolomicsP20HL113452 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI HAZEN, STANLEY L, TANG, WAI HONG WILSON · 2012 to 2016
$4.8M
Diet, Gut Microbiota, and Heart FailureR01HL126827 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI HAZEN, STANLEY L, TANG, WAI HONG WILSON · 2016 to 2019
$3.1M
CWRU NEPHROLOGY TRAINING PROGRAMT32DK007470 · NIDDK · CASE WESTERN RESERVE UNIVERSITY · PI SEDOR, JOHN R. · 1986 to 2019
$2.9M
Dietary Choline, Gut Microbiota, and Susceptibility for Chronic Kidney DiseaseR01DK106000 · NIDDK · CLEVELAND CLINIC LERNER COM-CWRU · PI HAZEN, STANLEY L, TANG, WAI HONG WILSON · 2015 to 2018
$2.8M
Collaborative Cross of the Microbiome and Metabolic DiseaseR01DK108259 · NIDDK · UNIVERSITY OF WISCONSIN-MADISON · PI REY, FEDERICO E · 2015 to 2019
$2.1M
Microbial Trimethylamine Lyases and AtherosclerosisR01HL130819 · NHLBI · CLEVELAND CLINIC LERNER COM-CWRU · PI WANG, ZENENG · 2016 to 2019
$1.7M
NHLBI NIH HHS P01 HL076491NHLBI NIH HHS P20 HL113452NHLBI NIH HHS R01 HL103866NHLBI NIH HHS R01 HL126827NHLBI NIH HHS R01 HL130819NIDDK NIH HHS R01 DK106000NIDDK NIH HHS R01 DK108259NIDDK NIH HHS T32 DK007470
6 · The paper itself

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.

Indexed as

MetabolomicsAgedAnimalsAtherosclerosisCardiovascular DiseasesCarnitineCholesterolCholineDisease Models, AnimalFecesFemaleGastrointestinal MicrobiomeGenome-Wide Association StudyHumansLysineMaleCarnitineCholesterolCholineLysineMethylaminesNutrientstrimethylaminetrimethyllysinetrimethyloxamineAtherosclerosisCardiologyCardiovascular diseaseCholesterolVascular Biology

Identifiers

PMID29563342
PMCPMC5926943
OpenAlexW2790593817

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.