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

Publisher: Elsevier Country of Publication: United States NLM ID: 0323470 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1523-1755 (Electronic) Linking ISSN: 00852538 NLM ISO Abbreviation: Kidney Int Subsets: MEDLINE

Publication: 2016- : New York : Elsevier
Original Publication: New York, Springer-Verlag.

Polymorphism, Single Nucleotide*; Amino Acid Transport Systems, Basic/*genetics ; Amino Acids/*urine ; Renal Insufficiency, Chronic/*epidemiology; Aged ; Biomarkers/urine ; Case-Control Studies ; Chi-Square Distribution ; Female ; Genetic Predisposition to Disease ; Glycine/urine ; Histidine/urine ; Humans ; Incidence ; Logistic Models ; Lysine/urine ; Male ; Mass Spectrometry ; Massachusetts/epidemiology ; Metabolomics/methods ; Middle Aged ; Odds Ratio ; Oligonucleotide Array Sequence Analysis ; Phenotype ; Proportional Hazards Models ; Prospective Studies ; Protective Factors ; Renal Insufficiency, Chronic/diagnosis ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/urine ; Risk Assessment ; Risk Factors ; Urinalysis ; omega-N-Methylarginine/urine

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 ² ) 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.
(Copyright © 2017 International Society of Nephrology. All rights reserved.)

Comment in: Kidney Int. 2017 Jun;91(6):1274-1276. (PMID: 28501300)

Keywords: chronic kidney disease; epidemiology; genetics; proximal tubule

0 (Amino Acid Transport Systems, Basic)
0 (Amino Acids)
0 (Biomarkers)
0 (SLC7A9 protein, human)
27JT06E6GR (omega-N-Methylarginine)
4QD397987E (Histidine)
K3Z4F929H6 (Lysine)
TE7660XO1C (Glycine)

Date Created: 20170318 Date Completed: 20180322 Latest Revision: 20220409

20240829

10.1016/j.kint.2017.01.007

28302371