Comparative Genome-Wide Association Studies in Mice and Humans for Trimethylamine N -Oxide, a Proatherogenic Metabolite of Choline and l -Carnitine
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Objective—: Elevated levels of plasma trimethylamine N -oxide (TMAO), the product of gut microbiome and hepatic-mediated metabolism of dietary choline and l -carnitine, have recently been identified as a novel risk factor for the development of atherosclerosis in mice and humans. The goal of this study was to identify the genetic factors associated with plasma TMAO levels. Approach and Results—: We used comparative genome-wide association study approaches to discover loci for plasma TMAO levels in mice and humans. A genome-wide association study in the hybrid mouse diversity panel identified a locus for TMAO levels on chromosome 3 ( P =2.37×10 −6 ) that colocalized with a highly significant ( P =1.07×10 −20 ) cis -expression quantitative trait locus for solute carrier family 30 member 7. This zinc transporter could thus represent 1 positional candidate gene responsible for the association signal at this locus in mice. A genome-wide association study for plasma TMAO levels in 1973 humans identified 2 loci with suggestive evidence of association ( P =3.0×10 −7 ) on chromosomes 1q23.3 and 2p12. However, genotyping of the lead variants at these loci in 1892 additional subjects failed to replicate their association with plasma TMAO levels. Conclusions—: The results of these limited observational studies indicate that, at least in humans, genes play a marginal role in determining TMAO levels and that any genetic effects are relatively weak and complex. Variation in diet or the repertoire of gut microbiota may be more important determinants of plasma TMAO levels in mice and humans, which should be investigated in future studies.
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Genetic variation seems to play a minor role in determining circulating levels of TMAO.
“genetic variation seems to play a minor role in determining the circulating levels of TMAO [15].”
From Microbiota‐dependent metabolite trimethylamine‐N‐oxide is associated with disease severity and survival of patients with chronic heart failure (2015) · cites this paper as [15]
A comparative GWAS found a mouse chromosome 3 locus for plasma TMAO (P < 0.001) that co-localized with a strong cis-eQTL for Slc30a7.
“We used a compara-tive GWAS approach to discover loci for plasma TMAO levels in mice and humans, and identified a locus for TMAO levels on chromosome 3 (P < 0.001) that co-localized with a highly significant (P < 0.001) cis-expression quantitative trait locus for solute carrier family 30 member 7 (Slc30a7) (60).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [60]
The zinc transporter Slc30a7 may be a positional candidate for the mouse association signal, but the GWAS associations are weak.
“Although this zinc transporter might represent a positional candidate gene responsible for the association signal at this locus in mice (60), these are weak associations in GWASs.”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [60]
FMO3 and TMAO were significantly correlated, and TMAO explained 11% of the variation in atherosclerosis among the inbred mouse strains studied.
“FMO3 and TMAO were significantly correlated, and TMAO levels accounted for 11% of the variation in atherosclerosis across the inbred strains of mice examined (60).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [60]
A human GWAS of plasma TMAO in 1,973 people found two loci with suggestive association (P < 0.001) on chromosomes 1q23.3 and 2p12, but genotyping lead variants in 1,892 more people did not replicate the association.
“Furthermore, GWASs for plasma TMAO levels in 1,973 humans identified 2 loci with suggestive evidence of association (P < 0.001) on chromosomes 1q23.3 and 2p12; however, genotyping of the lead variants at these loci in 1,892 additional subjects failed to replicate their association with plasma TMAO levels (60).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [60]
A genomewide association study found no significant host genetic influences on circulating TMAO and proposed that diet and gut microbes may be the main determinants of circulating TMAO.
“Although FMO3 and FMO1 genes are important in the formation of TMAO, a genomewide association study failed to find any significant host genetic influences on circulating TMAO concentrations and proposed that dietary factors and gut microbes may be the major determinants of circulating TMAO concentrations (49).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [49]
A genome-wide association study involving 1973 humans concluded that genes play only a marginal role in determining TMAO levels.
“Heritability of TMAO was studied in a genome-wide association study involving 1973 humans, which concluded that genes play only a marginal role in determining TMAO levels [20].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [20]
High levels of TMAO in patients with CKD (eGFR <60mL/min) portended a significantly increased mortality risk with HR 1.93 (95%CI 1.13-3.29).
“our group observed that high levels of TMAO in patients with CKD (defined as eGFR <60mL/min) portended a significantly increased mortality risk with HR 1.93 (95%CI 1.13–3.29)198.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [198]
In mice, chronic TMAO and choline feeding resulted in renal fibrosis and increased tubular injury markers such as cystatin C, pSMAD, and KIM-1/tubulin ratio.
“Translating findings to mice models, we observed that both chronic TMAO and choline feeding resulted in striking development of renal fibrosis, along with increased levels of tubular injury markers such as cystatin C, pSMAD, and KIM-1/tubulin ratio198.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [198]
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Trimethylamine N-Oxide From Gut Microbiota in Chronic Kidney Disease Patients: Focus on Diet
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Trimethylamine-N-oxide (TMAO) increased aquaporin-2 expression in spontaneously hypertensive rats
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Association between Plasma Trimethylamine N-Oxide Levels and Type 2 Diabetes: A Case Control Study
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Gut microbial metabolite TMAO portends prognosis in acute ischemic stroke
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The Possible Role of Probiotic Supplementation in Inflammation: A Narrative Review
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Intestinal Microbiota Metabolism and Atherosclerosis
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The Genetic Architecture of Coronary Artery Disease: Current Knowledge and Future Opportunities
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Self-citationUse of dietary phytochemicals for inhibition of trimethylamine N-oxide formation
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Diet and Gut Microbial Function in Metabolic and Cardiovascular Disease Risk
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Genomic Determinants of Hypertension With a Focus on Metabolomics and the Gut Microbiome
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microRNA-146a-5p association with the cardiometabolic disease risk factor TMAO
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Self-citationThe Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice
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Loop Diuretics Inhibit Renal Excretion of Trimethylamine N-Oxide
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- Authors
- Hartiala, J., Bennett, B. J., Tang, W. H. W., Wang, Z., Stewart, A. F. R., Roberts, R., McPherson, R., Lusis, A. J., Hazen, S. L., & Allayee, H.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2014-06
- Volume
- 34
- Issue
- 6
- Pages
- 1307-1313
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC4035110
- OpenAlex
- W2127621744
- Cited by
- 133
- References
- 32
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 12 · 2022: 12 · 2021: 12 · 2020: 10 · 2019: 13 · 2018: 8 · 2017: 12 · 2016: 14 · 2015: 16 · 2014: 6
- FWCI
- 10.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000130)
- Canadian Institutes of Health Research (MOT82810)
- National Heart, Lung, and Blood Institute (P01 HL-30568, P01HL030568, R00HL102223, R01HL103931, K99HL102223, P20HL113452, P01HL076491, P01HL098055, P01-HL28481, R01HL103866, P01HL028481)
- National Institute of Environmental Health Sciences (R01ES021801)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- trimethylamine N-oxide, choline metabolism, L-carnitine, gut microbiota, atherosclerosis risk, genetic susceptibility, zinc transporters, Hybrid Mouse Diversity Panel, plasma biomarkers, gene-diet interaction
- MeSH terms
- Aged, Animals, Carnitine, Choline, Chromosomes, Human, Pair 1, Female, Multigene Family, Humans, Male, Methylamines, Middle Aged, Oxygenases, Polymorphism, Single Nucleotide, Cation Transport Proteins, Mice, Genome-Wide Association Study
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