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Publication Information
Affiliation
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA. Electronic address: shengyuan.luo@jhu.edu.; Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas, USA.; Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.; Johns Hopkins Whiting School of Engineering, Baltimore, Maryland, USA.; Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.; McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.; Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.; Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas, USA.; Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA; Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Authors
Luo Shengyuan, Feofanova Elena V, Tin Adrienne, Tung Sarah, Rhee Eugene P, Coresh Josef, Arking Dan E, Surapaneni Aditya, Schlosser Pascal, Li Yong, Köttgen Anna, Yu Bing, Grams Morgan E
Studies
Abstract
The genome-wide association study (GWAS) is a powerful means to study genetic determinants of disease traits and generate insights into disease pathophysiology. To date, few GWAS of circulating metabolite levels have been performed in African Americans with chronic kidney disease. Hypothesizing that novel genetic-metabolite associations may be identified in a unique population of African Americans with a lower glomerular filtration rate (GFR), we conducted a GWAS of 652 serum metabolites in 619 participants (mean measured glomerular filtration rate 45 mL/min/1.73m2) in the African American Study of Kidney Disease and Hypertension, a clinical trial of blood pressure lowering and antihypertensive medication in African Americans with chronic kidney disease. We identified 42 significant variant metabolite associations. Twenty associations had been previously identified in published GWAS, and eleven novel associations were replicated in a separate cohort of 818 African Americans with genetic and metabolomic data from the Atherosclerosis Risk in Communities Study. The replicated novel variant-metabolite associations comprised eight metabolites and eleven distinct genomic loci. Nine of the replicated associations represented clear enzyme-metabolite interactions, with high expression in the kidneys as well as the liver. Three loci (ACY1, ACY3, and NAT8) were associated with a common pool of metabolites, acetylated amino acids, but with different individual affinities. Thus, extensive metabolite profiling in an African American population with chronic kidney disease aided identification of novel genome-wide metabolite associations, providing clues about substrate specificity and the key roles of enzymes in modulating systemic levels of metabolites.