1. Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics (SORA), Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
2. Department of Epidemiology and Public Health, Imperial College London, St Mary's Campus, London W2 1PG, UK
3. Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
4. Department of Public Health, Division of Epidemiology, Akademisch Ziekenhuis St Rafael, Leuven B-3000, Belgium
5. Department of Health Science, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
6. Department of Epidemiology, Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences, Beijing 100037, China
7. These authors contributed equally to this work.

Correspondence to: Jeremy K. Nicholson¹Paul Elliott² Correspondence and requests for materials should be addressed to J.K.N. (Email: j.nicholson@imperial.ac.uk) or P.E. (Email: p.elliott@imperial.ac.uk).

Abstract

Metabolic phenotypes are the products of interactions among a variety of factors—dietary, other lifestyle/environmental, gut microbial and genetic^{1, 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 activities^{2, 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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