Li, Yong and Sekula, Peggy and Wuttke, Matthias and Wahrheit, Judith and Hausknecht, Birgit and Schultheiss, Ulla T. and Gronwald, Wolfram and Schlosser, Pascal and Tucci, Sara and Ekici, Arif B. and Spiekerkoetter, Ute and Kronenberg, Florian and Eckardt, Kai-Uwe and Oefner, Peter J. and Koettgen, Anna (2018) Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 29 (5). pp. 1513-1524. ISSN 1046-6673, 1533-3450
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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=2.4x10(-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=6.6x10(-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=2.2x10(-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHRONIC KIDNEY-DISEASE; FRACTIONAL URATE EXCRETION; HUMAN BLOOD METABOLITES; QUALITY-CONTROL; MOLECULAR-CLONING; AMINO-ACIDS; ARRAY; GENE; OXIDASE; PROTEIN; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Feb 2020 13:32 |
| Last Modified: | 20 Feb 2020 13:32 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14612 |
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