title: Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease.
abstract: We assessed the association between urinary metabolites, genetic variants, and incident chronic kidney disease (CKD) in the Framingham Offspring cohort. Among the participants, 193 individuals developed CKD (estimated glomerular filtration rate under 60 ml/min/1.73m2) between cohort examinations 6 (1995-1998) and 8 (2005-2008, mean follow-up 9.7 years). They were age- and sex-matched to 193 control individuals free of CKD. A total of 154 urinary metabolites were measured using mass spectrometry, and the association between metabolites and CKD was examined using logistic regression. Next, we tested the genetic associations of each metabolite with an Illumina exome chip. Urinary glycine and histidine were associated with a lower risk of incident CKD with an odds ratio of 0.59 (95% confidence interval [CI] 0.43-0.80) and 0.65 (0.50-0.85) respectively, per one standard deviation increase in metabolite concentration. Follow-up in the Atherosclerosis Risk in Communities cohort confirmed the association of urinary glycine with CKD. In exome chip analyses, 36 single nucleotide polymorphisms at 30 loci were significantly associated with 31 metabolites. We surveyed exome chip findings for associations with known renal function loci such as rs8101881 in SLC7A9 coding for an amino acid transporter, which has been associated with a lower risk of CKD. We found this polymorphism was significantly associated with higher levels of lysine and NG-monomethyl-L-arginine (NMMA). Increased urinary lysine and NMMA were associated with a lower risk of CKD (0.73 [0.50-0.90] and 0.66 [0.53-0.83], respectively) in the univariate model. Thus, low urinary glycine and histidine are associated with incident CKD. Furthermore, genomic association of urinary metabolomics identified lysine and NMMA as being linked with CKD and provided additional evidence for the association of SLC7A9 with kidney disease.
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA; Division of Nephrology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Gearoid M
authors.initials: GM
authors.lastname: McMahon
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Tin
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA; Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.affiliation: Nephrology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Rhee
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA; Division of Nephrology, University of Utah, Salt Lake City, Utah, USA; Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA; Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA; Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
authors.forename: J Hunter
authors.initials: JH
authors.lastname: Young
authors.affiliation: Broad Institute, Cambridge, Massachusetts, USA; Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA; Division of Endocrinology and Metabolism, Brigham and Women's Hospital, Boston, Massachusetts, USA. Electronic address: foxca@nhlbi.nih.gov.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
mesh_terms: D000368:Aged; D026923:Amino Acid Transport Systems, Basic / Q000235:genetics*; D000596:Amino Acids / Q000652:urine*; D015415:Biomarkers / Q000652:urine; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D020022:Genetic Predisposition to Disease; D005998:Glycine / Q000652:urine; D006639:Histidine / Q000652:urine; D006801:Humans; D015994:Incidence; D016015:Logistic Models; D008239:Lysine / Q000652:urine; D008297:Male; D013058:Mass Spectrometry; D008404:Massachusetts / Q000453:epidemiology; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D065840:Protective Factors; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics / Q000652:urine; D018570:Risk Assessment; D012307:Risk Factors; D016482:Urinalysis; D019323:omega-N-Methylarginine / Q000652:urine
chemical_list: D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids; D015415:Biomarkers; C499489:SLC7A9 protein, human; D019323:omega-N-Methylarginine; D006639:Histidine; D008239:Lysine; D005998:Glycine
keywords: chronic kidney disease; epidemiology; genetics; proximal tubule