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Human metabolic phenotype diversity and its association with diet and blood pressure


Metabolic phenotypes are the products of interactions among a variety of factors—dietary, other lifestyle/environmental, gut microbial and genetic1,2,3. 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 worldwide4). We analyse spectra from two 24-hour urine specimens for each of 4,630 participants from the INTERMAP epidemiological study5, 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 pressure6. 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 activities2,7, 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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Figure 1: Hierarchical cluster analysis using group average linkage based on median 1 H NMR urine spectra, by population sample and gender ( n = 4,630).
Figure 2: Plots of cross-validated principal components analysis scores ( n = 4,630).
Figure 3: O-PLS-DA scores and loadings plots (bootstrap analyses) for participants reporting high vegetable/low animal protein and low vegetable/high animal protein intakes, first 24-h urinary specimens.


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INTERMAP is supported by the US National Heart, Lung, and Blood Institute (RO1 HL50490 and RO1 HL084228); the Chicago Health Research Foundation; and national agencies in Japan (the Ministry of Education, Science, Sports, and Culture), China and the UK. The funders had no role in the design and conduct of the study, or in the collection, management, analysis and interpretation of the data, or in the preparation, review or approval of the manuscript. The INTERMAP study has been accomplished through the work of the staff at the local, national and international centres. A partial listing of colleagues is in ref. 5. We thank M. Rantalanein, O. Cloarec, E. Want and O. Beckonert (Imperial College London) for their assistance with the statistical and NMR analyses; and P. Oefner and H. Kaspar (University of Regensburg) for gas chromatography mass spectrometry analyses.

Author Contributions The INTERMAP study was conceived by J.S., P.E. and Rose Stamler (deceased); INTERMAP urinary amino acids study was by J.S., P.E., M.L.D. and H.K.; INTERMAP metabonomics study was by J.K.N. and P.E., with E.H., and J.S., M.L.D. The manuscript was written by P.E., J.K.N., E.H. and J.S.; analyses were done by R.L.L., M.B., I.K.S.Y., Q.C. and I.J.B. T.E., M.D.I., and K.V. provided statistical and analytical support. H.U. and L.Z. were responsible for data collection. All authors reviewed and approved the manuscript.

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Correspondence to Jeremy K. Nicholson or Paul Elliott.

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Holmes, E., Loo, R., Stamler, J. et al. Human metabolic phenotype diversity and its association with diet and blood pressure. Nature 453, 396–400 (2008).

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