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Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms

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Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms CLINICAL RESEARCH www.jasn.org Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms Yong Li,1 Peggy Sekula ,1 Matthias Wuttke,1 Judith Wahrheit,2 Birgit Hausknecht,3 Ulla T. Schultheiss,1 Wolfram Gronwald,4 Pascal Schlosser ,1 Sara Tucci,5 Arif B. Ekici,6 Ute Spiekerkoetter,5 Florian Kronenberg ,7 Kai-Uwe Eckardt,3 Peter J. Oefner,4 and Anna Köttgen ,1 the GCKD Investigators Due to the number of contributing authors, the affiliations are listed at the end of this article. 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 con- centrations of 139 serum metabolites and 41 urine metabolites, as well as their pairwise ratios and frac- tional 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 2 polyamines (AOC1, P-min=2.4310 12), a relatively high carrier frequency (2%) for rare deleterious mis- sense variants in ACADM that are collectively associated with serum ratios of medium-chain acylcarnitines 2 (P-burden=6.6310 16), and associations of a common variant in SLC7A9 with several ratios of lysine to 2 neutral amino acids in urine, including the lysine/glutamine ratio (P=2.2310 23). The associations of this SLC7A9 variant with ratios of lysine to specific neutral amino acids were much stronger than the associ- ation 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. J Am Soc Nephrol 29: 1513–1524, 2018. doi: https://doi.org/10.1681/ASN.2017101099 CLINICAL RESEARCH Metabolites are small molecules that represent in- termediates or products of metabolic processes. Received October 16, 2017. Accepted February 9, 2018. They play important roles in energy generation, Y.L. and P.S. contributed equally to this work. signaling, and the regulation of enzymatic reactions. Published online ahead of print. Publication date available at The concentrations of these small molecules in cells www.jasn.org. and body fluids result from a balance of their intake Correspondence: Dr. Anna Köttgen, Institute of Genetic Epi- and generation, their transport across compart- demiology, Medical Center – University of Freiburg, Hugstetter ments, and their breakdown and excretion. The Straße 49, 79106 Freiburg, Germany. Email: anna.koettgen@ kidneys play a central role in all of these processes, uniklinik-freiburg.de providing a rationale for metabolomics research in Copyright © 2018 by the American Society of Nephrology J Am Soc Nephrol 29: 1513–1524, 2018 ISSN : 1046-6673/2905-1513 1513 CLINICAL RESEARCH www.jasn.org nephrology.1 Previous studies have linked blood metabolite Significance Statement concentrations to common genetic markers across the ge- nome and found a strong genetic component to the measured The kidney is a central organ for metabolite handling. Genetic concentrations of many metabolites.2–10 The implicated genes studies of metabolite concentrations in blood and urine from pa- are often involved in balancing blood metabolite concentrations tients with CKD may reveal aspects of metabolite handling. The authors carried out genome-wide association studies of 139 serum through metabolite generation (e.g., encoding the rate-limiting and 41 urine metabolites and their pairwise ratios among 1168 enzyme), turnover, or excretion (e.g., encoding metabolite patients with CKD. Of particular interest was an association between transporters). In CKD, reduced GFR leads to elevated concen- genetic variants in SLC7A9 and several urinary lysine–to–neutral trations of many metabolites in blood. We therefore hypothe- amino acid ratios. The associations match the biologic function of SLC7A9 sized that the presence of CKD represents a “challenge” model as a renal exchanger of cationic against neutral amino acids, and provide a direct human readout of its substrates in vivo. for metabolite handling. Under such a model, metabolites may The study highlights the potential of linking genomics to metab- be quantifiable that are usually below the limit of detection, and olomics to generate insights into human renal physiology. renal mechanisms that facilitate active metabolite reabsorption or excretion may be altered and could inform about tubular 2 functions. Studying metabolite concentrations in patients with had an eGFR between 30 and 60 ml/min per 1.73 m or an . 2 CKD may therefore allow for the detection of genetic loci influ- eGFR 60 ml/min per 1.73 m and a urinary albumin-to-cre- . encing such processes. atinine ratio (UACR) 300 mg/g, albuminuria 300 mg/d, a . Only a few previous studies have investigated genetic influ- urinary protein-to-creatinine ratio 500 mg/g, or proteinuria . 15 ences on metabolite concentrations in urine,11–13 which are of 500 mg/d. Trained personnel obtained information on particular interest for the field of nephrology. Not only does clinical data, socio-demographic factors, medical and family the urine contain metabolites that are exclusively or predom- history, medications, and health-related quality of life. The inantly generated in the kidneys and secreted into urine, but leading cause of CKD was ascertained from the treating ne- urinary metabolite concentrations also allow for the modeling phrologist. Moreover, biospecimens (plasma, serum, whole of specific renal functions that may be affected in the presence blood, spot urine) were collected in a standardized way at of CKD. For example, genetic screens for the metabolite’s frac- the enrollment visit, processed, and shipped frozen to a central tional excretion (FE) could identify tubular transport proteins laboratory for routine clinical chemistry and to a central for this metabolite, or genetic variants associated with the biobank for future analyses following standard operating pro- 16 ratio of metabolites in the urine could identify substrates cedures. A complete description of study design and the 14,15 that are counter-transported across the apical tubular cell recruited study population can be found elsewhere. membrane. For the current analysis, serum and urine specimens col- We therefore set out to test the following hypotheses: first, lected at baseline were selected for metabolite measurements genetic investigations of metabolite concentrations in serum from a subset of GCKD participants: all participants re- and urine of patients with CKD can replicate findings from cruited from the Freiburg study center and additionally previous population-based studies and identify additional ge- all GCKD patients from other study centers with autoso- netic loci that may reflect the metabolic challenge posed by mal-dominant polycystic kidney disease, focal segmental CKD. Second, modeling of kidney-specific functions on the glomerulosclerosis, membranous nephropathy, membrano- basis of metabolite concentrations can be used to gain insights proliferative GN, rapid progressive GN, pauci-immune, and – into tubular transport mechanisms and metabolic reactions of anti glomerular basement membrane GN as the leading importance in CKD or detectable in its presence. To test these cause of CKD (Supplemental Material). hypotheses in a proof-of-principle study, we carried out ge- nome-wide association studies (GWAS) of metabolite concen- Genotyping and Imputation trations in serum and urine as well as their FEs and pairwise Genomic DNA was extracted from whole blood using an au- ratios in up to 1168 patients with CKD participating in the tomated magnetic bead–based technology, quantified and German Chronic Kidney Disease (GCKD) study.14 normalized on a pipetting robot platform, and available for 5123 GCKD participants. Genotyping was conducted for 2,612,357 markers at the Helmholtz Center Munich using METHODS Omni2.5Exome BeadChip arrays (Illumina, GenomeStudio, Genotyping Module Version 1.9.4). Data cleaning was carried Study Design and Participants out separately for the Omni2.5 content and the Exome Chip The GCKD study is a prospective cohort study of patients with content of the array. For the Omni2.5 content, data QC and CKD treated by nephrologists. It was approved by the local cleaning followed the protocol of Anderson et al.17 Per-indi- ethics committees and registered in the national registry for vidual QC steps included evaluation of call rate, sex check, clinical studies (DRKS 00003971). Between 2010 and 2012, heterozygosity, cryptic relatedness, and genetic ancestry. Alto- 5217 eligible adult patients provided written consent and gether, 89 individuals were removed during the per-individual were enrolled into the study.14 Patients were included if they QC. In the per–single nucleotide polymorphism (SNP) QC 1514
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