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Original ArticlesChronic Kidney Disease
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NAT8 Variants, N-Acetylated Amino Acids, and Progression of CKD

Shengyuan Luo, Aditya Surapaneni, Zihe Zheng, Eugene P. Rhee, Josef Coresh, Adriana M. Hung, Girish N. Nadkarni, Bing Yu, Eric Boerwinkle, Adrienne Tin, Dan E. Arking, Inga Steinbrenner, Pascal Schlosser, Anna Köttgen and Morgan E. Grams
CJASN January 2021, 16 (1) 37-47; DOI: https://doi.org/10.2215/CJN.08600520
Shengyuan Luo
1Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
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Aditya Surapaneni
1Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
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Zihe Zheng
3Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Eugene P. Rhee
4Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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Josef Coresh
1Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
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Adriana M. Hung
5Geriatric Research Education Clinical Center, Veteran Administration Tennessee Valley Health Care System, Nashville, Tennessee
6Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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Girish N. Nadkarni
7The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
8Bio Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, New York
9Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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Bing Yu
10Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Sciences Center at Houston School of Public Health, Houston, Texas
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Eric Boerwinkle
10Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Sciences Center at Houston School of Public Health, Houston, Texas
11Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas
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Adrienne Tin
1Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
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Dan E. Arking
12McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Inga Steinbrenner
13Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
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Pascal Schlosser
13Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
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Anna Köttgen
1Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
13Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
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Morgan E. Grams
1Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
14Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
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Abstract

Background and objectives Genetic variants in NAT8, a liver- and kidney-specific acetyltransferase encoding gene, have been associated with eGFR and CKD in European populations. Higher circulating levels of two NAT8-associated metabolites, N-δ-acetylornithine and N-acetyl-1-methylhistidine, have been linked to lower eGFR and higher risk of incident CKD in the Black population. We aimed to expand upon prior studies to investigate associations between rs13538, a missense variant in NAT8, N-acetylated amino acids, and kidney failure in multiple, well-characterized cohorts.

Design, setting, participants, & measurements We conducted analyses among participants with genetic and/or serum metabolomic data in the African American Study of Kidney Disease and Hypertension (AASK; n=962), the Atherosclerosis Risk in Communities (ARIC) study (n=1050), and BioMe, an electronic health record–linked biorepository (n=680). Separately, we evaluated associations between rs13538, urinary N-acetylated amino acids, and kidney failure in participants in the German CKD (GCKD) study (n=1624).

Results Of 31 N-acetylated amino acids evaluated, the circulating and urinary levels of 14 were associated with rs13538 (P<0.05/31). Higher circulating levels of five of these N-acetylated amino acids, namely, N-δ-acetylornithine, N-acetyl-1-methylhistidine, N-acetyl-3-methylhistidine, N-acetylhistidine, and N2,N5-diacetylornithine, were associated with kidney failure, after adjustment for confounders and combining results in meta-analysis (combined hazard ratios per two-fold higher amino acid levels: 1.48, 1.44, 1.21, 1.65, and 1.41, respectively; 95% confidence intervals: 1.21 to 1.81, 1.22 to 1.70, 1.08 to 1.37, 1.29 to 2.10, and 1.17 to 1.71, respectively; all P values <0.05/14). None of the urinary levels of these N-acetylated amino acids were associated with kidney failure in the GCKD study.

Conclusions We demonstrate significant associations between an NAT8 gene variant and 14 N-acetylated amino acids, five of which had circulation levels that were associated with kidney failure.

  • AASK (African American Study of Kidney Disease and Hypertension)
  • chronic kidney disease
  • end-stage renal disease
  • human genetics
  • metabolism
  • amino acids
  • acetylation
  • Received May 29, 2020.
  • Accepted November 4, 2020.
  • Copyright © 2021 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 16 (1)
Clinical Journal of the American Society of Nephrology
Vol. 16, Issue 1
January 07, 2021
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NAT8 Variants, N-Acetylated Amino Acids, and Progression of CKD
Shengyuan Luo, Aditya Surapaneni, Zihe Zheng, Eugene P. Rhee, Josef Coresh, Adriana M. Hung, Girish N. Nadkarni, Bing Yu, Eric Boerwinkle, Adrienne Tin, Dan E. Arking, Inga Steinbrenner, Pascal Schlosser, Anna Köttgen, Morgan E. Grams
CJASN Jan 2021, 16 (1) 37-47; DOI: 10.2215/CJN.08600520

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NAT8 Variants, N-Acetylated Amino Acids, and Progression of CKD
Shengyuan Luo, Aditya Surapaneni, Zihe Zheng, Eugene P. Rhee, Josef Coresh, Adriana M. Hung, Girish N. Nadkarni, Bing Yu, Eric Boerwinkle, Adrienne Tin, Dan E. Arking, Inga Steinbrenner, Pascal Schlosser, Anna Köttgen, Morgan E. Grams
CJASN Jan 2021, 16 (1) 37-47; DOI: 10.2215/CJN.08600520
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Keywords

  • AASK (African American Study of Kidney Disease and Hypertension)
  • chronic kidney disease
  • end-stage renal disease
  • human genetics
  • metabolism
  • amino acids
  • acetylation

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