TY - JOUR
T1 - A metabolome-wide association study of kidney function and disease in the general population
AU - Sekula, Peggy
AU - Goek, Oemer Necmi
AU - Quaye, Lydia
AU - Barrios, Clara
AU - Levey, Andrew S.
AU - Römisch-Margl, Werner
AU - Menni, Cristina
AU - Yet, Idil
AU - Gieger, Christian
AU - Inker, Lesley A.
AU - Gronwald, Wolfram
AU - Illig, Thomas
AU - Dettmer, Katja
AU - Krumsiek, Jan
AU - Oefner, Peter J.
AU - Valdes, Ana M.
AU - Meisinger, Christa
AU - Coresh, Josef
AU - Spector, Tim D.
AU - Mohney, Robert P.
AU - Suhre, Karsten
AU - Kastenmüller, Gabi
AU - Köttgen, Anna
N1 - Funding Information:
This study was supported in part by grants from the German Federal Ministry of Education and Research (BMBF) to the German Center Diabetes Research and from the European Commission Seventh Framework Programme (EurHEALTHAging Small-Scale Focused Research Collaborative Project 277849). The KORA research platform was initiated and financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the state of Bavaria. The TwinsUK study was funded by the Wellcome Trust and the European Commission Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research–funded BioResource Clinical Research Facility and Biomedical Research Centre based at Guy’s and St. Thomas’ National Health Service Foundation Trust, in partnership with King’s College London. Metabolomic analysis in the TwinsUK study was funded by Pfizer. The work of P.S., O.-N.G., and A.K. was funded by the Emmy Noether Program of the German Research Foundation (KO 3598/ 2-1 to A.K.) and the BMBF (Gerontosys II NephAge Project, 031 5896 A). C.B. is supported by a grant from the Spanish Society of Nephrology. W.R.-M. is supported by funds from the Helmholtz Association Cross Program Initiative in Individualized Medicine. J.K. is supported by a grant from the Helmholtz Postdoctoral Programme Initiative and Networking Fund. K.S. was supported by Biomedical Research Program funds at Weill Cornell Medical College in Qatar, a program funded by the Qatar Foundation. The work of J.C., L.A.I., and A.S.L. was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK097020).
Publisher Copyright:
Copyright © 2016 by the American Society of Nephrology.
PY - 2016
Y1 - 2016
N2 - 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 m2) 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.
AB - 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 m2) 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.
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U2 - 10.1681/ASN.2014111099
DO - 10.1681/ASN.2014111099
M3 - Article
C2 - 26449609
AN - SCOPUS:85017080584
SN - 1046-6673
VL - 27
SP - 1175
EP - 1188
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
IS - 4
ER -