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. 2016 Aug 11;11(8):e0161074.
doi: 10.1371/journal.pone.0161074. eCollection 2016.

Association of FMO3 Variants and Trimethylamine N-Oxide Concentration, Disease Progression, and Mortality in CKD Patients

Free PMC article

Association of FMO3 Variants and Trimethylamine N-Oxide Concentration, Disease Progression, and Mortality in CKD Patients

Cassianne Robinson-Cohen et al. PLoS One. .
Free PMC article


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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.


Fig 1
Fig 1. Scatterplot of plasma TMAO concentration versus estimated GFR for subjects with FMO3 E/E (open square) and FMO3 E/K or K/K (closed circle) allelic variants.
TMAO concentration increases as eGFR decreases, with greater rate of increase observed with eGFR < 40 mL/min/1.73m2. Dashed line indicates the Lowess curve for reference allele homozygous subjects (158 E/E). Dotted line indicates the Lowess curve for heterozygous or variant homozygous subjects (158 E/K or K/K).

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    1. Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. The New England journal of medicine. 2005;352(20):2049–60. Epub 2005/05/20. 10.1056/NEJMoa043161 . - DOI - PubMed
    1. Sarnak MJ, Katz R, Stehman-Breen CO, Fried LF, Jenny NS, Psaty BM, et al. Cystatin C concentration as a risk factor for heart failure in older adults. Annals of internal medicine. 2005;142(7):497–505. Epub 2005/04/06. . - PubMed
    1. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. The New England journal of medicine. 2004;351(13):1285–95. Epub 2004/09/24. 10.1056/NEJMoa041365 . - DOI - PubMed
    1. Tang WH, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B, et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circulation research. 2015;116(3):448–55. Epub 2015/01/20. 10.1161/CIRCRESAHA.116.305360 - DOI - PMC - PubMed
    1. Stubbs JR, House JA, Ocque AJ, Zhang S, Johnson C, Kimber C, et al. Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden. Journal of the American Society of Nephrology: JASN. 2015. Epub 2015/08/01. ASN.2014111063 [pii] 10.1681/ASN.2014111063 . - DOI - PMC - PubMed

Grant support

These studies were supported by a grant from the Norman S. Coplon Extramural Grant Program by Satellite Healthcare, a not-for-profit renal care provider National Institute of Health (CKY), and the National Institutes of Health National Center for Advancing Translational Sciences Grant KL2 TR000421 (CKY). The authors also acknowledge The University of Washington Kidney Research Institute, supported by an unrestricted gift from the Northwest Kidney. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.