title: 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 (1)H 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-h urine specimens per person for 523 northern and 244 southern Chinese participants in the INTERMAP Study of macro/micronutrients and blood pressure. 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 minimize 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, and methylguanidine; metabolites significantly (P < 1.1 × 10(-12) to 2 × 10(-127)) higher in the south were gut microbial cometabolites (hippurate, 4-cresyl sulfate, phenylacetylglutamine, 2-hydroxyisobutyrate), succinate, creatine, scyllo-inositol, prolinebetaine, and trans-aconitate. These findings indicate the importance of environmental influences (e.g., diet), endogenous metabolism, and mammalian-gut microbial cometabolism, which may help explain north-south China differences in cardiovascular disease risk.
authors.affiliation: Department of Surgery and Cancer, Faculty of Medicine, School of Public Health, Imperial College London, United Kingdom.
authors.forename: Ivan K S
authors.initials: IK
authors.lastname: Yap
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Brown
authors.forename: Queenie
authors.initials: Q
authors.lastname: Chan
authors.forename: Anisha
authors.initials: A
authors.lastname: Wijeyesekera
authors.forename: Isabel
authors.initials: I
authors.lastname: Garcia-Perez
authors.forename: Magda
authors.initials: M
authors.lastname: Bictash
authors.forename: Ruey Leng
authors.initials: RL
authors.lastname: Loo
authors.forename: Marc
authors.initials: M
authors.lastname: Chadeau-Hyam
authors.forename: Timothy
authors.initials: T
authors.lastname: Ebbels
authors.forename: Maria
authors.initials: M
authors.lastname: De Iorio
authors.forename: Elaine
authors.initials: E
authors.lastname: Maibaum
authors.forename: Liancheng
authors.initials: L
authors.lastname: Zhao
authors.forename: Hugo
authors.initials: H
authors.lastname: Kesteloot
authors.forename: Martha L
authors.initials: ML
authors.lastname: Daviglus
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Stamler
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
mesh_terms: D000328:Adult; D000597:Amino Acids, Branched-Chain / Q000652:urine; D044466:Asian People / Q000706:statistics & numerical data; D015415:Biomarkers / Q000652:urine*; D002318:Cardiovascular Diseases / Q000208:ethnology / Q000652:urine*; D002681:China; D003401:Creatine / Q000652:urine; D016002:Discriminant Analysis; D005260:Female; D005843:Geography; D006801:Humans; D016018:Least-Squares Analysis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D019158:N-Acetylneuraminic Acid / Q000652:urine; D018570:Risk Assessment / Q000706:statistics & numerical data; D012307:Risk Factors; D019802:Succinic Acid / Q000652:urine; D058949:Uromodulin / Q000652:urine
chemical_list: D000597:Amino Acids, Branched-Chain; D015415:Biomarkers; D058949:Uromodulin; D019802:Succinic Acid; D019158:N-Acetylneuraminic Acid; D003401:Creatine