What is the clinical evidence from this study?

Study design: Cohort. Population: Cardiovascular disease risk (n=1356). Primary outcome: Epigenome-wide association study (EWAS) of DNA methylation CpGs associated with plasma levels of TMAO and related metabolites (FDR < 0.05 for 143 metabolite-CpG pairs (4 CpGs for TMAO, 12 for betaine, 53 for γ-butyrobetaine, 5 for carnitine, 6 for choline, 63 for crotonobetaine), p=P ≤ 4.03e-7 for TMAO CpGs).

What does this research mean for the field?

Trimethylamine N-oxide is associated with significant changes in DNA methylation, which may contribute to cardiovascular disease risk. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The aim is to explore how TMAO and related metabolites affect DNA methylation and, consequently, cardiovascular disease risk.

February 11, 2026Clinical Epigenetics0 citationsOpen Access

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

Q: What are the key findings of this study?

TMAO and related metabolites were associated with 143 DNA methylation CpG sites at FDR <0.05, implicating epigenetic mechanisms linked to cardiovascular disease risk.

Q: What does this research mean for the field?

Trimethylamine N-oxide is associated with significant changes in DNA methylation, which may contribute to cardiovascular disease risk. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

The aim is to explore how TMAO and related metabolites affect DNA methylation and, consequently, cardiovascular disease risk.

JMJiantao MaTufts University CLChao-Qiang LaiTufts University XLXinmin S. LiCleveland Clinic

Key Result

TMAO and related metabolites were associated with 143 DNA methylation CpG sites at FDR <0.05, implicating epigenetic mechanisms linked to cardiovascular disease risk.

Key Points

The aim is to explore how TMAO and related metabolites affect DNA methylation and, consequently, cardiovascular disease risk.
Identified specific DNA methylation sites associated with TMAO and related metabolites.
Examined potential pathways linking these changes to cardiovascular disease risk.
Found specific DNA methylation alterations related to TMAO levels.
Suggests a connection between these changes and increased risk for cardiovascular disease.

Study Design

Type

Cohort (n=1,356)

Multicenter

Yes

Structured PICO

Are circulating levels of TMAO and related metabolites associated with specific DNA methylation changes in adults?

Population

1,356 adults from two multi-center, community-based prospective cohort studies: the Cardiovascular Health Study (CHS, n=430) and the Multi-Ethnic Study of Atherosclerosis (MESA, n=926). CHS participants: mean age 77 years, 63% women. MESA participants: mean age 60 years, 53% women. Diverse sample of U.S. adults including European American, African American, Hispanic American, and Chinese American participants.

Intervention

Circulating levels of Trimethylamine N-oxide (TMAO) and five related metabolites (betaine, γ-butyrobetaine, carnitine, choline, and crotonobetaine) quantified by stable-isotope dilution liquid chromatography with on-line electrospray ionization tandem mass spectrometry (LC-MS).

Outcome

DNA methylation levels across approximately 430,000 CpG sites measured using Illumina BeadChip arrays (Epigenome-wide association study).surrogate

TMAO and its related metabolites are associated with specific DNA methylation changes that may causally influence cardiovascular disease risk, highlighting a potential epigenetic mechanism linking diet, gut microbiome, and CVD.

Main Result

Effect estimate: FDR < 0.05 for 143 metabolite-CpG pairs (4 CpGs for TMAO, 12 for betaine, 53 for γ-butyrobetaine, 5 for carnitine, 6 for choline, 63 for crotonobetaine)

p-value: P ≤ 4.03e-7 for TMAO CpGs

Limitations

Observational study design limits causal inference despite Mendelian randomization analyses.
DNA methylation measured in whole blood which may not reflect other relevant tissues.
Cross-sectional nature limits ability to determine temporality of associations.
Cohorts predominantly from United States, which may limit generalizability to other populations.

Abstract

This 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.

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