1. Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms
- Author
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Florian Kronenberg, Birgit Hausknecht, Pascal Schlosser, Judith Wahrheit, Kai-Uwe Eckardt, Ulla T. Schultheiss, Peggy Sekula, Yong Li, Peter J. Oefner, Matthias Wuttke, Arif B. Ekici, Sara Tucci, Ute Spiekerkoetter, Wolfram Gronwald, and Anna Köttgen more...
- Subjects
Adult ,Male ,0301 basic medicine ,Glutamine ,Metabolite ,Population ,Genome-wide association study ,Acyl-CoA Dehydrogenase ,03 medical and health sciences ,chemistry.chemical_compound ,Clinical Research ,Carnitine ,Up Front Matters ,Putrescine ,Humans ,Prospective Studies ,Renal Insufficiency, Chronic ,education ,ACADM ,Aged ,chemistry.chemical_classification ,education.field_of_study ,Lysine ,Biological Transport ,General Medicine ,Middle Aged ,Apical membrane ,Lipid Metabolism ,Amino acid ,Kidney Tubules ,030104 developmental biology ,chemistry ,Biochemistry ,Genetic Loci ,Nephrology ,Renal physiology ,Metabolome ,Amino Acid Transport Systems, Basic ,Female ,Amine Oxidase (Copper-Containing) ,Genome-Wide Association Study - 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(−12)), 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(−16)), 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(−23)). 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. more...
- Published
- 2018
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