Metabolome-Wide Association Study Identifies Multiple Biomarkers that Discriminate North and South Chinese Populations at Differing Risks of Cardiovascular Disease: INTERMAP Study

Abstract

Rates of heart disease and stroke vary markedly between north and south China. A 1H NMR spectroscopy-based Metabolome-Wide Association approach was used to identify urinary metabolites that discriminate between southern and northern Chinese population samples, to investigate population biomarkers that might relate to the difference in cardiovascular disease risk. NMR spectra were acquired from two 24-hour urine specimens per person for 523 northern and 244 southern Chinese participants in the INTERMAP Study of macro/micronutrients and BP. Discriminating metabolites were identified using Orthogonal Partial Least Squares Discriminant Analysis and assessed for statistical significance with conservative Family Wise Error Rate <0.01 to minimise false positive findings. Urinary metabolites significantly (P <1.2×10−16 to 2.9×10−69) higher in northern than southern Chinese populations included dimethylglycine, alanine, lactate, branched-chain amino acids (isoleucine, leucine, valine), N-acetyls of glycoprotein fragments (including uromodulin), N-acetyl neuraminic acid, pentanoic/heptanoic acid, methylguanidine; metabolites significantly (P <1.1×10−12 to 2×10−127) higher in the south were gut microbial co-metabolites (hippurate, 4-cresyl sulphate, phenylacetylglutamine; 2-hydroxyisobutyrate), succinate, creatine, scyllo-inositol, prolinebetaine, trans-aconitate. These findings indicate the importance of environmental influences (e.g., diet), endogenous metabolism and mammalian-gut microbial co-metabolism, that may help explain north-south China differences in cardiovascular disease risk.

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