A Metabolome-Wide Association Study of Kidney Function and Disease in the General Population

被引:164
作者
Sekula, Peggy [1 ,2 ]
Goek, Oemer-Necmi [1 ]
Quaye, Lydia [3 ]
Barrios, Clara [3 ,4 ]
Levey, Andrew S. [5 ]
Roemisch-Marg, Werner [7 ]
Menni, Cristina [3 ]
Yet, Idil [3 ]
Gieger, Christian [6 ]
Inker, Lesley A. [5 ]
Adamski, Jerzy [8 ,11 ,12 ]
Gronwald, Wolfram
Illig, Thomas [14 ,15 ]
Dettmer, Katja [13 ]
Krumsiek, Jan [9 ,16 ]
Oefner, Peter J.
Valdes, Ana M. [2 ,16 ]
Meisinger, Christa [10 ]
Coresh, Josef [17 ]
Spector, Tim D. [3 ]
Mohney, Robert P. [18 ]
Suhre, Karsten [19 ]
Kastenmueller, Gabi [3 ,7 ]
Koettgen, Anna [1 ]
机构
[1] Univ Freiburg, Med Ctr, Div Nephrol, Berliner Allee 29, D-79110 Freiburg, Germany
[2] Univ Freiburg, Med Ctr, Ctr Med Biometry & Med Informat, D-79110 Freiburg, Germany
[3] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England
[4] Hosp del Mar, Dept Nephrol, Inst Mar Invest Med, Barcelona, Spain
[5] Tufts Med Ctr, Div Nephrol, Boston, MA USA
[6] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, D-85764 Neuherberg, Germany
[7] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Bioinformat & Syst Biol, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany
[8] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Genome Anal Ctr, Inst Expt Genet, D-85764 Neuherberg, Germany
[9] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Computat Biol, D-85764 Neuherberg, Germany
[10] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, D-85764 Neuherberg, Germany
[11] German Ctr Diabet Res, Neuherberg, Germany
[12] Tech Univ Munich, Inst Expt Genet, Freising Weihenstephan, Germany
[13] Univ Regensburg, Inst Funct Genom, D-93053 Regensburg, Germany
[14] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany
[15] Hannover Med Sch, Inst Human Genet, Hannover, Germany
[16] Univ Nottingham, Acad Rheumatol, Nottingham NG7 2RD, England
[17] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA
[18] Metabolon Inc, Durham, NC USA
[19] Weill Cornell Med Coll Qatar, Dept Physiol & Biophys, Doha, Qatar
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2016年 / 27卷 / 04期
基金
美国国家卫生研究院; 英国惠康基金;
关键词
PROTEIN C-MANNOSYLATION; SERUM CREATININE; UREMIC PATIENTS; RENAL-DISEASE; GENOME-WIDE; PSEUDOURIDINE; ACCUMULATION; RISK; CALIBRATION; EXCRETION;
D O I
10.1681/ASN.2014111099
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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 eG FRcr, 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.
引用
收藏
页码:1175 / 1188
页数:14
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