Association of FMO3 Variants and Trimethylamine N-Oxide Concentration, Disease Progression, and Mortality in CKD Patients
Open accessAbstract
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.
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Most study participants were from Europe and the United States and included mainly approximately 65-90% whites.
“Fifth, most of the study participants were from Europe and the United States and included mainly (approximately of 65–90% of total study participants) whites,10, 19, 20, 23 so that our results might not be applicable to other race/ethnic groups such as Asians and Africans.”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [23]
These observations have been replicated in multiple independent observational cohorts across a spectrum of CKD patients.
“These observations have since been replicated in multiple independent observational cohorts across a spectrum of CKD patients199–203.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [199]
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Cites
Toprak, Ö., Kurt, H., Sarı, Y., Şarkış, C., Us, H., & Kırık, A. (2017) · Kidney & Blood Pressure Research · doi:10.1159/000468530 · Cited by 29,769 · see citing works
A New Equation to Estimate Glomerular Filtration Rate
Levey, A. S., Stevens, L. A., Schmid, C. H., Zhang, Y. (., Castro, A. F., Feldman, H. I., Kusek, J. W., Eggers, P., Van Lente, F., Greene, T., et al. (2009) · Annals of Internal Medicine · doi:10.7326/0003-4819-150-9-200905050-00006 · Cited by 25,603 · see citing works
Longitudinal data analysis for discrete and continuous outcomes.
Zeger, S., & Liang, K.-Y. (1986) · Biometrics · doi:10.2307/2531248 · Cited by 8,044 · see citing works
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597 · see citing works
Dialysis Dose and Intradialytic Hypotension: Results from the HEMO Study
Causland, F. R. M., Brunelli, S. M., & Waikar, S. S. (2013) · American Journal of Nephrology · doi:10.1159/000355958 · Cited by 2,705 · see citing works
Relation between Renal Dysfunction and Cardiovascular Outcomes after Myocardial Infarction
Anavekar, N. S., McMurray, J. J. V., Velazquez, E. J., Solomon, S. D., Køber, L., Rouleau, J. L., White, H. D., Nordlander, R., Maggioni, A. P., Dickstein, K., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa041365 · Cited by 1,913 · see citing works
Cystatin C and the Risk of Death and Cardiovascular Events among Elderly Persons
Shlipak, M. G., Sarnak, M. J., Katz, R., Fried, L. F., Seliger, S. L., Newman, A. B., Siscovick, D. S., & Stehman‐Breen, C. O. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa043161 · Cited by 1,241 · see citing works
Tang, W. H. W., Wang, Z., Kennedy, D. J., Wu, Y., Buffa, J. A., Agatisa-Boyle, B., Li, X. S., Levison, B. S., & Hazen, S. L. (2015) · Circulation Research · doi:10.1161/circresaha.116.305360 · Cited by 1,223 · see citing works
Craig, S. A. (2004) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/80.3.539 · Cited by 1,062 · see citing works
Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden
Stubbs, J. R., House, J. A., Ocque, A. J., Zhang, S., Johnson, C., Kimber, C., Schmidt, K., Gupta, A., Wetmore, J. B., Nolin, T. D., et al. (2016) · Journal of the American Society of Nephrology · doi:10.1681/asn.2014111063 · Cited by 450 · see citing works
The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
Warrier, M., Shih, D. M., Burrows, A. C., Ferguson, D., Gromovsky, A. D., Brown, A. L., Marshall, S., McDaniel, A., Schugar, R. C., Wang, Z., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2014.12.036 · Cited by 414 · see citing works
Shih, D. M., Wang, Z., Lee, R., Meng, Y., Che, N., Charugundla, S., Qi, H., Wu, J., Pan, C., Brown, J. M., et al. (2015) · Journal of Lipid Research · doi:10.1194/jlr.m051680 · Cited by 335 · see citing works
A Prospective Study of Frailty in Nephrology-Referred Patients With CKD
Roshanravan, B., Khatri, M., Robinson-Cohen, C., Levin, G. P., Patel, K., de Boer, I. D., Seliger, S., Ruzinski, J., Himmelfarb, J., & Kestenbaum, B. (2012) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2012.05.017 · Cited by 315 · see citing works
Self-citationCystatin C Concentration as a Risk Factor for Heart Failure in Older Adults
Sarnak, M. J., Katz, R., Stehman‐Breen, C. O., Fried, L. F., Jenny, N. S., Psaty, B. M., Newman, A. B., Siscovick, D. S., Shlipak, M. G., & Study*, A. T. C. H. (2005) · Annals of Internal Medicine · doi:10.7326/0003-4819-142-7-200504050-00008 · Cited by 313 · see citing works
Lang, D., Yeung, C., Peter, R., Ibarra, C., Gasser, R., Itagaki, K., Philpot, R., & Rettie, A. (1998) · Biochemical Pharmacology · doi:10.1016/s0006-2952(98)00218-4 · Cited by 303 · see citing works
Self-citationTreacy, E. P. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.5.839 · Cited by 228 · see citing works
Kaysen, G. A., Johansen, K. L., Chertow, G. M., Dalrymple, L. S., Kornak, J., Grimes, B., Dwyer, T., Chassy, A. W., & Fiehn, O. (2015) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2015.02.006 · Cited by 164 · see citing works
Physical activity and change in estimated GFR among persons with CKD.
Robinson-Cohen, C., Littman, A. J., Duncan, G., Weiss, N. S., Sachs, M. C., Ruzinski, J., Kundzins, J., Rock, D., de Boer, I. D., Ikizler, T., et al. (2014) · Journal of the American Society of Nephrology · doi:10.1681/asn.2013040392 · Cited by 150 · see citing works
Self-citationBell, J. D., Lee, J. A., Lee, H. A., Sadler, P. J., Wilkie, D. R., & Woodham, R. H. (1991) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/0925-4439(91)90046-c · Cited by 147 · see citing works
S-oxidation of thioureylenes catalyzed by a microsomal flavoprotein mixed-function oxidase
Poulsen, L. L., Hyslop, R. M., & Ziegler, D. M. (1974) · Biochemical Pharmacology · doi:10.1016/0006-2952(74)90346-3 · Cited by 144 · see citing works
Mild trimethylaminuria caused by common variants in FM03 gene
Zschocke, J., Kohlmueller, D., Quak, E., Meißner, T., Hoffmann, G. F., & Mayatepek, E. (1999) · The Lancet · doi:10.1016/s0140-6736(99)80019-1 · Cited by 109 · see citing works
Chemical chaperones assist intracellular folding to buffer mutational variations
Bandyopadhyay, A., Saxena, K., Kasturia, N., Dalal, V., Bhatt, N. R., Rajkumar, A., Maity, S., Sengupta, S., & Chakraborty, K. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.768 · Cited by 101 · see citing works
Trimethylaminuria: causes and diagnosis of a socially distressing condition.
Mackay, R. J., McEntyre, C. J., Henderson, C., Lever, M., & George, P. M. (2011) · Europe PMC (PubMed Central) · Cited by 94 · see citing works
Trimethylaminuria Is Caused by Mutations of the FMO3 Gene in a North American Cohort
Akerman, B. R., Lemass, H., Chow, L. M. L., Lambert, D. M., Greenberg, C. R., Bibeau, C., Mamer, O., & Treacy, E. P. (1999) · Molecular Genetics and Metabolism · doi:10.1006/mgme.1999.2885 · Cited by 78 · see citing works
Koukouritaki, S. B., Poch, M. T., Henderson, M. C., Siddens, L. K., Krueger, S. K., VanDyke, J. E., Williams, D. E., Pajewski, N. M., Wang, T., & Hines, R. N. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.112268 · Cited by 69 · see citing works
Functional characterization of genetic variants of human FMO3 associated with trimethylaminuria
Yeung, C. K., Adman, E. T., & Rettie, A. E. (2007) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2007.04.014 · Cited by 68 · see citing works
Self-citationTreacy, E. P., Johnson, D. W., Pitt, J. J., et al. (1994) · Journal of Inherited Metabolic Disease · doi:10.1007/bf00710420 · Cited by 56 · see citing works
Woods, J. S., Heyer, N. J., Russo, J. E., Martin, M. D., & Farin, F. M. (2014) · NeuroToxicology · doi:10.1016/j.neuro.2014.07.010 · Cited by 48 · see citing works
Assessment of Physical Activity in Chronic Kidney Disease
Robinson‐Cohen, C., Littman, A. J., Duncan, G. E., Roshanravan, B., Ikizler, T. A., Himmelfarb, J., & Kestenbaum, B. R. (2012) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2012.04.008 · Cited by 47 · see citing works
Self-citationFish odour syndrome: Verification of carrier detection test
Zhang, A. Q., Mitchell, S., & Smith, R. (1995) · Journal of Inherited Metabolic Disease · doi:10.1007/bf02436755 · Cited by 44 · see citing works
Bushueva, O. Y., Solodilova, M. A., Churnosov, M. I., Ivanov, V. P., & Polonikov, A. (2014) · International Journal of Hypertension · doi:10.1155/2014/712169 · Cited by 41 · see citing works
Molecular evolution and balancing selection in the flavin-containing monooxygenase 3 gene (FMO3)
Allerston, C. K., Shimizu, M., Fujieda, M., Shephard, E. A., Yamazaki, H., & Phillips, I. R. (2007) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e328256b198 · Cited by 33 · see citing works
Echeverria, D., Woods, J. S., Heyer, N. J., Martin, M. D., Rohlman, D. S., Farin, F. M., & Li, T. (2010) · Journal of Toxicology and Environmental Health · doi:10.1080/15287390903566591 · Cited by 30 · see citing works
Dolan, C., Shields, D. C., Stanton, A. V., O'Brien, E. T., Lambert, D. M., O’Brien, J., & Treacy, E. P. (2005) · BMC Medical Genetics · doi:10.1186/1471-2350-6-41 · Cited by 23 · see citing works
Mao, M., Matimba, A., Scordo, M. G., et al. (2009) · Pharmacogenomics · doi:10.2217/pgs.09.77 · Cited by 19 · see citing works
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Research works printed but not linked: 2
- [16]Treacy E, Johnson D, Pitt JJ, Danks DM. Trimethylaminuria, fish odour syndrome: a new method of detection and response to treatment with metronidazole. Journal of inherited metabolic disease. 1995; 18(3): 306– 12. Epub 1995/01/01.. 7474897
- [24]Robinson-Cohen C, Littman AJ, Duncan GE, Weiss NS, Sachs MC, Ruzinski J, et al Physical activity and change in estimated GFR among persons with CKD. Journal of the American Society of Nephrology: JASN. 2014; 25(2): 399– 406. Epub 2013/12/18. 10.1681/ASN.2013040392 ASN.2013040392 [pii]. 24335971 PMC3904564 · DOI
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Tang, W. H. W., Li, D. Y., & Hazen, S. L. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0108-7 · Cited by 789 · see citing works
Heianza, Y., Ma, W., Manson, J. E., Rexrode, K. M., & Qi, L. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.116.004947 · Cited by 544 · see citing works
Li, X. S., Obeid, S., Klingenberg, R., Gencer, B., Mach, F., Räber, L., Windecker, S., Rodondi, N., Nanchen, D., Muller, O., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehw582 · Cited by 479 · see citing works
- Authors
- Robinson-Cohen, C., Newitt, R., Shen, D. D., Rettie, A. E., Kestenbaum, B. R., Himmelfarb, J., & Yeung, C. K.
- Affiliations
- University of Washington (US)
- Corresponding author
- Yeung, Catherine K.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-08-11
- Volume
- 11
- Issue
- 8
- Pages
- e0161074
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4981377
- OpenAlex
- W2507227271
- Cited by
- 63
- References
- 35
- Citations by year
- 2026: 8 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 9 · 2021: 5 · 2020: 9 · 2019: 4 · 2018: 3 · 2017: 9 · 2016: 2
- FWCI
- 7.50
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Center for Advancing Translational Sciences (KL2 TR000421)
- Norman S. Coplon Extramural Grant Program by Satellite Healthcare
- The University of Washington Kidney Research Institute, supported by an unrestricted gift from the Northwest Kidney Centers
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- FMO3, trimethylamine N-oxide, chronic kidney disease, genetic polymorphism, uremic solutes, cardiovascular risk, estimated glomerular filtration rate decline, mortality, disease progression
- MeSH terms
- Female, Humans, Male, Methylamines, Middle Aged, Oxygenases, Prognosis, Prospective Studies, Biomarkers, Survival Rate, Disease Progression, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic
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