Evidence map›Paper›PMID 41656272›Full record

ArticleClinical epigenetics2026

Trimethylamine N-oxide and related metabolites may regulate DNA methylation and trigger cardiovascular disease.

Jiantao Ma, Chao-Qiang Lai, Xinmin S Li, Meng Wang, Zeneng Wang, Jie Yao, Xiuqing Guo, Kent D Taylor, Soyoung Lee, Russell P Tracy and 16 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Clinical epigenetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
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

3 citing papers in PubMed.

  1. Review
  2. Article
  3. Review
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

26 authors.

Jiantao Ma *Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
Chao-Qiang Lai *USDA ARS, Jean Mayer USDA Human Nutrition Research Center On Aging, Boston, MA, USA.
Xinmin S LiDepartment of Heart, Blood and Kidney Research, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Meng WangFriedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
Zeneng WangDepartment of Heart, Blood and Kidney Research, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Jie YaoDepartment of Pediatrics, The Institute for Translational Genomics and Population Sciences, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Xiuqing GuoDepartment of Pediatrics, The Institute for Translational Genomics and Population Sciences, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Kent D TaylorDepartment of Pediatrics, The Institute for Translational Genomics and Population Sciences, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Soyoung LeeFriedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
Russell P TracyDepartment of Pathology & Laboratory Medicine, University of Vermont Larner College of Medicine, 360 South Park Drive, Colchester, VT, 05446, USA.
Durda PeterDepartment of Pathology & Laboratory Medicine, University of Vermont Larner College of Medicine, 360 South Park Drive, Colchester, VT, 05446, USA.
Yongmei LiuDuke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Jerome I RotterDepartment of Pediatrics, The Institute for Translational Genomics and Population Sciences, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Stephen S RichDepartment of Genome Sciences, University of Virginia School of Medicine, 1200 Jefferson Park Avenue, Charlottesville, VA, 22903, USA.
Matthew BudoffDepartment of Medicine, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
WHWilson TangDepartment of Heart, Blood and Kidney Research, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Joseph A DiDonatoDepartment of Heart, Blood and Kidney Research, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Rozenn N LemaitreCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Amanda FrettsCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Nona SotoodehniaCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Bruce M PsatyCardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA, USA.
José M OrdovásJean Mayer USDA Human Nutrition Research Center On Aging, Boston, MA, USA.
David S SiscovickNew York Academy of Medicine, New York, NY, USA.
Stanley L HazenDepartment of Heart, Blood and Kidney Research, Learner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Dariush MozaffarianFriedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA. Dariush.Mozaffarian@tufts.edu.

Funding

Infrastructure for mentored access to CHS data and specimensR01HL172803 · NHLBI · UNIVERSITY OF WASHINGTON · PI James S Floyd, Michelle Christina Odden · 2025 to 2026
$2.7M
NHLBI NIH HHS P01HL147823 and R01HL103866NHLBI NIH HHS R01 HL135920-5NHLBI NIH HHS R01 HL172803
6 · The paper itself

Abstract

backgroundTrimethylamine N-oxide (TMAO) and its related metabolites have been linked to cardiovascular disease (CVD), but their impact on DNA methylation remains unclear. Investigating these relationships may clarify the role of epigenetic mechanisms in diseases.

methodsThis study analyzed data from 1,356 adults from the Cardiovascular Health Study (CHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Using stable-isotope dilution liquid chromatography with on-line electrospray ionization tandem mass spectrometry (LC-MS), we quantified TMAO and five related metabolites. DNA methylation levels were measured using Illumina BeadChip arrays. Epigenome-wide association analyses and meta-analyses were conducted across approximately 430,000 CpG sites. To explore the functional significance of the identified CpGs, we performed gene set enrichment analysis and Mendelian randomization (MR) analyses.

resultsWe identified 143 metabolite-CpG pairs at FDR < 0.05, including four CpGs for TMAO (P ≤ 4.03e-7), 12 for betaine (P ≤ 1.19e-6), 53 for γ-butyrobetaine (P ≤ 6.11e-6), five for carnitine (P ≤ 5.42e-7), six for choline (P ≤ 2.81e-7), and 63 for crotonobetaine (P ≤ 7.25e-6). CpGs associated with γ-butyrobetaine showed moderate correlation with crotonobetaine-associated CpGs. In total, these metabolite-linked CpGs were mapped to 108 genes. Gene set enrichment analysis revealed 145 significantly enriched gene sets, including nine highly relevant to CVD risk. Furthermore, CpGs were enriched in 80 immunologic signature gene sets (FDR < 0.05). MR analysis identified three CpGs associated with coronary artery disease (CAD), including hypermethylation at cg18705301 (NDUFAF1), which was inversely associated with betaine levels and linked to a lower risk of CAD (P = 1.8e-5).

conclusionThis study identified specific DNA methylation sites associated with TMAO and related metabolites. These epigenetic changes may contribute to CVD risk through multiple pathways. Future research should validate these findings and explore their clinical implications.

Indexed as

Cardiovascular DiseasesDNA MethylationMethylaminesAgedBetaineCarnitineCholineCpG IslandsEpigenesis, GeneticFemaleGenome-Wide Association StudyHumansMaleMiddle AgedBetaineCarnitineCholinegamma-butyrobetaineMethylaminestrimethyloxamine

Identifiers

PMID41656272
PMCPMC12983797

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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.