title: A Metabolome-Wide Association Study of Kidney Function and Disease in the General Population.
abstract: Small molecules are extensively metabolized and cleared by the kidney. Changes in serum metabolite concentrations may result from impaired kidney function and can be used to estimate filtration (e.g., the established marker creatinine) or may precede and potentially contribute to CKD development. Here, we applied a nontargeted metabolomics approach using gas and liquid chromatography coupled to mass spectrometry to quantify 493 small molecules in human serum. The associations of these molecules with GFR estimated on the basis of creatinine (eGFRcr) and cystatin C levels were assessed in ≤1735 participants in the KORA F4 study, followed by replication in 1164 individuals in the TwinsUK registry. After correction for multiple testing, 54 replicated metabolites significantly associated with eGFRcr, and six of these showed pairwise correlation (r≥0.50) with established kidney function measures: C-mannosyltryptophan, pseudouridine, N-acetylalanine, erythronate, myo-inositol, and N-acetylcarnosine. Higher C-mannosyltryptophan, pseudouridine, and O-sulfo-L-tyrosine concentrations associated with incident CKD (eGFRcr <60 ml/min per 1.73 m(2)) in the KORA F4 study. In contrast with serum creatinine, C-mannosyltryptophan and pseudouridine concentrations showed little dependence on sex. Furthermore, correlation with measured GFR in 200 participants in the AASK study was 0.78 for both C-mannosyltryptophan and pseudouridine concentration, and highly significant associations of both metabolites with incident ESRD disappeared upon adjustment for measured GFR. Thus, these molecules may be alternative or complementary markers of kidney function. In conclusion, our study provides a comprehensive list of kidney function-associated metabolites and highlights potential novel filtration markers that may help to improve the estimation of GFR.
authors.affiliation: Division of Nephrology and Center for Medical Biometry and Medical Informatics, Medical Center-University of Freiburg, Freiburg, Germany;
authors.forename: Peggy
authors.initials: P
authors.lastname: Sekula
authors.affiliation: Division of Nephrology and.
authors.forename: Oemer-Necmi
authors.initials: ON
authors.lastname: Goek
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom;
authors.forename: Lydia
authors.initials: L
authors.lastname: Quaye
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom; Department of Nephrology, Hospital del Mar, Institut Mar d'Investigacions Mediques, Barcelona, Spain;
authors.forename: Clara
authors.initials: C
authors.lastname: Barrios
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, Massachusetts;
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levey
authors.affiliation: Institutes of Bioinformatics and Systems Biology.
authors.forename: Werner
authors.initials: W
authors.lastname: Römisch-Margl
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom;
authors.forename: Cristina
authors.initials: C
authors.lastname: Menni
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom;
authors.forename: Idil
authors.initials: I
authors.lastname: Yet
authors.affiliation: Research Unit of Molecular Epidemiology and.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, Massachusetts;
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Inker
authors.affiliation: Experimental Genetics, Genome Analysis Center, German Center for Diabetes Research, Neuherberg, Germany; Institute of Experimental Genetics, Technical University of Munich, Freising-Weihenstephan, Germany;
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Institute of Functional Genomics, University of Regensburg, Regensburg, Germany;
authors.forename: Wolfram
authors.initials: W
authors.lastname: Gronwald
authors.affiliation: Research Unit of Molecular Epidemiology and Hannover Unified Biobank and Institute for Human Genetics, Hannover Medical School, Hannover, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.affiliation: Institute of Functional Genomics, University of Regensburg, Regensburg, Germany;
authors.forename: Katja
authors.initials: K
authors.lastname: Dettmer
authors.affiliation: Computational Biology, and.
authors.forename: Jan
authors.initials: J
authors.lastname: Krumsiek
authors.affiliation: Institute of Functional Genomics, University of Regensburg, Regensburg, Germany;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom; Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom;
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.affiliation: Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany;
authors.forename: Christa
authors.initials: C
authors.lastname: Meisinger
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland;
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom;
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Metabolon Inc., Durham, North Carolina; and.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.affiliation: Institutes of Bioinformatics and Systems Biology, Department of Physiology and Biophysics, Weill Cornell Medical College-Qatar, Doha, Qatar.
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom; Institutes of Bioinformatics and Systems Biology, German Center for Diabetes Research, Neuherberg, Germany; anna.koettgen@uniklinik-freiburg.de g.kastenmueller@helmholtz-muenchen.de.
authors.forename: Gabi
authors.initials: G
authors.lastname: Kastenmüller
authors.affiliation: Division of Nephrology and anna.koettgen@uniklinik-freiburg.de g.kastenmueller@helmholtz-muenchen.de.
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
mesh_terms: D003430:Cross-Sectional Studies; D005260:Female; D055106:Genome-Wide Association Study; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D055442:Metabolome / Q000235:genetics; D008875:Middle Aged; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
keywords: CKD; GFR; epidemiology; metabolism; outcomes