Human metabolic phenotype diversity and its association with diet and blood pressure
Open accessAbstract
Metabolic phenotypes are the products of interactions among a variety of factors-dietary, other lifestyle/environmental, gut microbial and genetic. We use a large-scale exploratory analytical approach to investigate metabolic phenotype variation across and within four human populations, based on 1H NMR spectroscopy. Metabolites discriminating across populations are then linked to data for individuals on blood pressure, a major risk factor for coronary heart disease and stroke (leading causes of mortality worldwide). We analyse spectra from two 24-hour urine specimens for each of 4,630 participants from the INTERMAP epidemiological study, involving 17 population samples aged 40-59 in China, Japan, UK and USA. We show that urinary metabolite excretion patterns for East Asian and western population samples, with contrasting diets, diet-related major risk factors, and coronary heart disease/stroke rates, are significantly differentiated (P < 10(-16)), as are Chinese/Japanese metabolic phenotypes, and subgroups with differences in dietary vegetable/animal protein and blood pressure. Among discriminatory metabolites, we quantify four and show association (P < 0.05 to P < 0.0001) of mean 24-hour urinary formate excretion with blood pressure in multiple regression analyses for individuals. Mean 24-hour urinary excretion of alanine (direct) and hippurate (inverse), reflecting diet and gut microbial activities, are also associated with blood pressure of individuals. Metabolic phenotyping applied to high-quality epidemiological data offers the potential to develop an area of aetiopathogenetic knowledge involving discovery of novel biomarkers related to cardiovascular disease risk.
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TMAO is also found in high levels in the urine of Japanese populations, who do not have high risk for CVD.
“However, TMAO is also found in high levels in the urine of Japanese populations, [38] who do not have high risk for CVD.”
From The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level (2018) · cites this paper as [38]
Metabolome-wide association studies (MWASs) have been proposed as useful tools for discovering low-molecular-weight biomarkers predictive of causal exposures or disease progression.
“MWASs have been proposed as useful tools for discovering low-molecular-weight biomarkers that are predictive of either causal exposures or disease progression (59, 165, 166).”
From The food metabolome: a window over dietary exposure (2014) · cites this paper as [59]
In the INTERMAP study, untargeted NMR of more than 4000 urine specimens from geographically diverse populations showed that metabolite concentrations differed substantially between Asian and Western populations.
“The investigators showed that metabolite concentrations differed substantially between Asian and Western populations, suggesting important effects of diet and related risk factors, including the microbiota, on the risk of coronary artery disease and stroke.”
From The food metabolome: a window over dietary exposure (2014) · cites this paper as [59]
The INTERMAP metabolite differences suggest important effects of diet and related risk factors, including microbiota, on coronary artery disease and stroke risk.
“The investigators showed that metabolite concentrations differed substantially between Asian and Western populations, suggesting important effects of diet and related risk factors, including the microbiota, on the risk of coronary artery disease and stroke.”
From The food metabolome: a window over dietary exposure (2014) · cites this paper as [59]
Potentially useful biomarkers may be identified through rigorous comparisons of quantitative or semiquantitative profiles of biospecimens from subjects with and without a particular disease.
“In either case, potentially useful biomarkers may be identified through rigorous comparisons of quantitative or semiquantitative profiles of biospecimens obtained from subjects with and without a particular disease (59).”
From The food metabolome: a window over dietary exposure (2014) · cites this paper as [59]
Three highly discriminating biomarkers were identified in the INTERMAP study: alanine was directly correlated with blood pressure, while formate and hippurate were inversely correlated with blood pressure.
“biomarkers were identified, namely alanine, which was directly correlated with blood pressure, and formate and hippurate, both of which were inversely correlated with blood pressure.”
From The food metabolome: a window over dietary exposure (2014) · cites this paper as [59]
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- Authors
- Holmes, E., Loo, R. L., Stamler, J., Bictash, M., Yap, I. K. S., Chan, Q., Ebbels, T., De Iorio, M., Brown, I. J., Veselkov, K. A., Daviglus, M. L., Kesteloot, H., Ueshima, H., Zhao, L., Nicholson, J. K., & Elliott, P.
- Affiliations
- Imperial College London (GB)
- Northwestern University (US)
- Shiga University of Medical Science (JP)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Nicholson, Jeremy K.
- Elliott, Paul
- ORCID
- Venue
- Nature
- Published
- 2008-04-20
- Volume
- 453
- Issue
- 7193
- Pages
- 396-400
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6556779
- OpenAlex
- W2013036395
- Cited by
- 1,054
- References
- 35
- Citations by year
- 2026: 14 · 2025: 27 · 2024: 17 · 2023: 32 · 2022: 36 · 2021: 61 · 2020: 49 · 2019: 49 · 2018: 75 · 2017: 60 · 2016: 91 · 2015: 59 · 2014: 88 · 2013: 86 · 2012: 72
- FWCI
- 32.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Murdoch University Research Portal (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Kent Academic Repository (University of Kent) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL050490, R01HL084228)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Health, Environment, Cognitive Aging
- Keywords
- urinary metabolic profiling, blood pressure, alanine, hippurate, diet, gut microbiota, cardiovascular risk, 24-hour urine, biomarkers, East Asian populations, coronary artery disease, stroke
- MeSH terms
- Adult, Alanine, Animals, Blood Pressure, Cardiovascular Diseases, China, Diet, Dietary Proteins, Female, United Kingdom, Hippurates, Humans, Intestines, Japan, Male, Metabolism, Middle Aged, Magnetic Resonance Spectroscopy, Phenotype, Time Factors, United States, Vegetables, Principal Component Analysis
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