Back to Search
Start Over
Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms.
- Source :
-
Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2018 May; Vol. 29 (5), pp. 1513-1524. Date of Electronic Publication: 2018 Mar 15. - Publication Year :
- 2018
-
Abstract
- Background The kidneys have a central role in the generation, turnover, transport, and excretion of metabolites, and these functions can be altered in CKD. Genetic studies of metabolite concentrations can identify proteins performing these functions. Methods We conducted genome-wide association studies and aggregate rare variant tests of the concentrations of 139 serum metabolites and 41 urine metabolites, as well as their pairwise ratios and fractional excretions in up to 1168 patients with CKD. Results After correction for multiple testing, genome-wide significant associations were detected for 25 serum metabolites, two urine metabolites, and 259 serum and 14 urinary metabolite ratios. These included associations already known from population-based studies. Additional findings included an association for the uremic toxin putrescine and variants upstream of an enzyme catalyzing the oxidative deamination of polyamines ( AOC1 , P -min=2.4×10 <superscript>-12</superscript> ), a relatively high carrier frequency (2%) for rare deleterious missense variants in ACADM that are collectively associated with serum ratios of medium-chain acylcarnitines ( P -burden=6.6×10 <superscript>-16</superscript> ), and associations of a common variant in SLC7A9 with several ratios of lysine to neutral amino acids in urine, including the lysine/glutamine ratio ( P =2.2×10 <superscript>-23</superscript> ). The associations of this SLC7A9 variant with ratios of lysine to specific neutral amino acids were much stronger than the association with lysine concentration alone. This finding is consistent with SLC7A9 functioning as an exchanger of urinary cationic amino acids against specific intracellular neutral amino acids at the apical membrane of proximal tubular cells. Conclusions Metabolomic indices of specific kidney functions in genetic studies may provide insight into human renal physiology.<br /> (Copyright © 2018 by the American Society of Nephrology.)
- Subjects :
- Acyl-CoA Dehydrogenase genetics
Adult
Aged
Amine Oxidase (Copper-Containing) genetics
Amino Acid Transport Systems, Basic metabolism
Carnitine analogs & derivatives
Carnitine metabolism
Female
Genetic Loci
Genome-Wide Association Study
Glutamine urine
Humans
Lipid Metabolism physiology
Lysine urine
Male
Metabolome
Middle Aged
Prospective Studies
Putrescine metabolism
Amino Acid Transport Systems, Basic genetics
Biological Transport genetics
Kidney Tubules metabolism
Renal Insufficiency, Chronic physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1533-3450
- Volume :
- 29
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of the American Society of Nephrology : JASN
- Publication Type :
- Academic Journal
- Accession number :
- 29545352
- Full Text :
- https://doi.org/10.1681/ASN.2017101099