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

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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-d-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 circulatingand urinarylevels of 14 were associated withrs13538 (P<0.05/31). Higher circulating levels of five of these N-acetylated amino acids, namely, N-d-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.

Original languageEnglish
Pages (from-to)37-47
Number of pages11
JournalClinical Journal of the American Society of Nephrology
Issue number1
StatePublished - Jan 2021


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