Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms
Li Y, Sekula P, Wuttke M, Wahrheit J, Hausknecht B, Schultheiss UT, Gronwald W, Schlosser P, Tucci S, Ekici AB, Spiekerkoetter U, Kronenberg F, Eckardt KU, Oefner PJ, Koettgen A (2018)
Publication Type: Journal article
Publication year: 2018
Journal
Book Volume: 29
Pages Range: 1513-1524
Journal Issue: 5
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.
Authors with CRIS profile
Arif Bülent Ekici
Institute of Human Genetics
Kai-Uwe Eckardt
Department of Medicine 4 – Nephrology and Hypertension
Involved external institutions
Biocrates Life Sciences AG
Austria (AT)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
Universität Regensburg
Germany (DE)
Medizinische Universität Innsbruck
Austria (AT)
Austria (AT)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
Universität Regensburg
Germany (DE)
Medizinische Universität Innsbruck
Austria (AT)
How to cite
APA:
Li, Y., Sekula, P., Wuttke, M., Wahrheit, J., Hausknecht, B., Schultheiss, U.T.,... Koettgen, A. (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), 1513-1524. https://dx.doi.org/10.1681/ASN.2017101099
MLA:
Li, Yong, et al. "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 (2018): 1513-1524.
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