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Urinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease.

TitleUrinary metabolites along with common and rare genetic variations are associated with incident chronic kidney disease.
Publication TypeJournal Article
Year of Publication2017
AuthorsMcMahon GM, Hwang S-J, Clish CB, Tin A, Yang Q, Larson MG, Rhee EP, Li M, Levy D, O'Donnell CJ, Coresh JJ, Young HJ, Gerszten RE
Secondary AuthorsFox CS
Corporate AuthorsCKDGen Consortium
JournalKidney Int
Date Published2017 06
KeywordsAged, Amino Acid Transport Systems, Basic, Amino Acids, Biomarkers, Case-Control Studies, Chi-Square Distribution, Female, Genetic Predisposition to Disease, Glycine, Histidine, Humans, Incidence, Logistic Models, Lysine, Male, Mass Spectrometry, Massachusetts, Metabolomics, Middle Aged, Odds Ratio, Oligonucleotide Array Sequence Analysis, omega-N-Methylarginine, Phenotype, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prospective Studies, Protective Factors, Renal Insufficiency, Chronic, Risk Assessment, Risk Factors, Urinalysis

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/1.73m) 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.

Alternate JournalKidney Int
PubMed ID28302371