title: Association of FMO3 Variants and Trimethylamine N-Oxide Concentration, Disease Progression, and Mortality in CKD Patients.
abstract: Elevated levels of circulating pro-atherogenic uremic solutes, particularly trimethylamine N-oxide (TMAO), have been implicated in cardiovascular disease development in patients with chronic kidney disease (CKD). TMAO is generated from trimethylamine (TMA) via metabolism by hepatic flavin-containing monooxygenase isoform 3 (FMO3). We determined the functional effects of three common FMO3 variants at amino acids 158, 308, and 257 on TMAO concentrations in a prospective cohort study and evaluated associations of polymorphisms with CKD progression and mortality. Each additional minor allele at amino acid 158 was associated with a 0.38 μg/mL higher circulating TMAO (p = 0.01) and with faster rates of annualized relative eGFR decline. Participants with 0, 1 and 2 variant alleles averaged an eGFR loss of 8%, 12%, and 14% per year, respectively (p-for trend = 0.05). Compared to participants with the homozygous reference allele, heterozygous and homozygous variant participants had a 2.0-fold (95% CI: 0.85, 4.6) and 2.2-fold (95% CI: 0.89, 5.48) higher risk of mortality, respectively (p-for-trend = 0.04). No associations with clinical outcomes were observed for allelic variants at amino acids 257 or 308. Understanding the contribution of genetic variation of FMO3 to disease progression and all-cause mortality can guide recommendations for diet modification or pharmacotherapy in CKD patients at increased risk of adverse outcomes.
authors: Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, 98195, United States of America.
authors: Cassianne
authors: C
authors: Robinson-Cohen
authors: Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, 98195, United States of America.
authors: Richard
authors: R
authors: Newitt
authors: Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, 98195, United States of America.
authors: Danny D
authors: DD
authors: Shen
authors: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington, 98195, United States of America.
authors: Allan E
authors: AE
authors: Rettie
authors: Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, 98195, United States of America.
authors: Bryan R
authors: BR
authors: Kestenbaum
authors: Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, 98195, United States of America.
authors: Jonathan
authors: J
authors: Himmelfarb
authors: Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, 98195, United States of America.|Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington, 98195, United States of America.
authors: Catherine K
authors: CK
authors: Yeung
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008744:Methylamines / Q000097:blood*; D008875:Middle Aged; D010105:Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D015996:Survival Rate
chemical_list: D015415:Biomarkers; D008744:Methylamines; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C005855:trimethyloxamine