Volume 11, Issue 3 (Vol.11 No.3 Oct 2022)                   rbmb.net 2022, 11(3): 430-439 | Back to browse issues page

XML Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Shorudi Dadi I, Saravani R, Khalili T, Sargazi* S, Majidpour M, Sarhadi M, et al . Coding Variants of the FMO3 Gene Are Associated with the Risk of Chronic Kidney Disease: A Case-Control Study. rbmb.net 2022; 11 (3) :430-439
URL: http://rbmb.net/article-1-925-en.html
Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran & Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran.
Abstract:   (1453 Views)
Background: Chronic kidney disease (CKD) is a global health concern involving roughly one-tenth of developed countries' populations. The flavin-containing dimethylaniline monooxygenase 3 (FMO3) gene encodes an enzyme that catalyzes trimethylamine N-oxide (TMAO), a toxin in CKD sufferers. This preliminary study aims to evaluate the association between coding region variations of FMO3, rs2266782G/A (E158K), rs2266780A/G (E308G), and rs1736557G/A (V257M), and the susceptibility to CKD.

Methods: A total of 356 participants were enrolled, including 157 patients diagnosed with CKD and 199 age-matched healthy individuals. Genotyping of FMO3 gene variations was performed via PCR-RFLP and ARMS-PCR methods.

Results: Our findings revealed a significant association between rs2266780A/G and rs1736557G/A and CKD under different genetic models. Compared to the GGG haplotype of rs2266782/rs1736557/rs2266780, the GAG, GAA, AAG, and AAA haplotype combinations conferred an increased risk of CKD in our population. Interaction analysis revealed that some genotype combinations, including GA/AA/AA, AA/AA/AA, GA/AA/GA, and GG/AG/AA, dramatically increased CKD risk in the Iranian population. No correlation was found between FMO3 polymorphisms and CKD stages.

Conclusions: These observations highlight the potential impact of coding variants of the FMO3 gene on the onset of CKD. Further investigations into expanded populations and diverse races are needed to confirm our findings.
Full-Text [PDF 315 kb]   (909 Downloads)    
Type of Article: Original Article | Subject: Molecular Biology
Received: 2022/04/23 | Accepted: 2022/05/8 | Published: 2022/12/31

1. Shawky SA, Gaber O, Mostafa E, Sarhan WM. Uncoupling Protein 2 Expression Modulates Obesity in Chronic Kidney Disease Patients. Reports of Biochemistry & Molecular Biology. 2021;10(1):119. [DOI:10.52547/rbmb.10.1.119] [PMID] [PMCID]
2. Aref HF, Naji NA, Ibrahim HD. Evaluation of Serum Cyclooxygenase, Hepcidin Levels in Acute Renal Injury (AKI) Patients Following Cardiac Catheterization. Reports of Biochemistry & Molecular Biology. 2021;10(2):197. [DOI:10.52547/rbmb.10.2.197] [PMID] [PMCID]
3. Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Glazer NL, et al. New loci associated with kidney function and chronic kidney disease. Nature genetics. 2010;42(5):376-84. [DOI:10.1038/ng.568] [PMID] [PMCID]
4. Wang H, Naghavi M, Allen C, Barber RM, Bhutta ZA, Carter A, et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. The lancet. 2016;388(10053):1459-544. https://doi.org/10.1016/S0140-6736(16)31575-6 [DOI:10.1016/S0140-6736(16)31012-1] [PMID]
5. Chand S, Chue CD, Edwards NC, Hodson J, Simmonds MJ, Hamilton A, et al. Endothelial nitric oxide synthase single nucleotide polymorphism and left ventricular function in early chronic kidney disease. PLoS One. 2015;10(1):e0116160. [DOI:10.1371/journal.pone.0116160] [PMID] [PMCID]
6. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau J-L, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. New England Journal of Medicine. 2004;351(13):1285-95. [DOI:10.1056/NEJMoa041365] [PMID]
7. Sargazi S, Mollashahi B, Sargazi S, Heidari Nia M, Saravani R, Mirinejad S, et al. Prevalence of miR146a gene polymorphisms in diabetic and non-diabetic patients with chronic kidney disease. Iranian Journal of Science and Technology, Transactions A: Science. 2022;46(1):21-31. [DOI:10.1007/s40995-021-01229-7]
8. Sargazi FM, Alidadi A, Taheri H, Nia MH, Sargazi S, Saravani R, et al. Functional miR29a gene polymorphism enhanced the risk of chronic kidney disease in an Iranian population: A preliminary case-control study and bioinformatics analyses. Meta Gene. 2020;25:100755. [DOI:10.1016/j.mgene.2020.100755]
9. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney international. 2011;80(12):1258-70. [DOI:10.1038/ki.2011.368] [PMID]
10. Xu J, Guo Z, Bai Y, Zhang J, Cui L, Zhang H, et al. Single nucleotide polymorphisms in the D-loop region of mitochondrial DNA is associated with the kidney survival time in chronic kidney disease patients. Renal Failure. 2015;37(1):108-12. [DOI:10.3109/0886022X.2014.976132] [PMID]
11. Garcia-Garcia G, Jha V. Chronic kidney disease in disadvantaged populations. Brazilian Journal of Medical and Biological Research. 2015;48:377-81. [DOI:10.1590/1414-431x20144519] [PMID] [PMCID]
12. Jahantigh D, Mirani Sargazi F, Sargazi S, Saravani R, Ghazaey Zidanloo S, Heidari Nia M, et al. Relationship between functional miR-143/145 cluster variants and susceptibility to type 2 diabetes mellitus: A preliminary case-control study and bioinformatics analyses. Endocrine Research. 2021;46(3):129-39. [DOI:10.1080/07435800.2021.1914079] [PMID]
13. Sargazi S, Heidari Nia M, Mirani Sargazi F, Sheervalilou R, Saravani R, Bahrami S, et al. Functional miR143/145 cluster variants and haplotypes are associated with chronic kidney disease: a preliminary case-control study and computational analyses. Applied Biochemistry and Biotechnology. 2021;193(5):1532-44. [DOI:10.1007/s12010-021-03489-w] [PMID]
14. 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. 2016;27(1):305-13. [DOI:10.1681/ASN.2014111063] [PMID] [PMCID]
15. Robinson-Cohen C, Newitt R, Shen DD, Rettie AE, Kestenbaum BR, Himmelfarb J, et al. Association of FMO3 variants and trimethylamine N-oxide concentration, disease progression, and mortality in CKD patients. PloS one. 2016;11(8):e0161074. [DOI:10.1371/journal.pone.0161074] [PMID] [PMCID]
16. Bell JD, Lee J, Lee H, Sadler PJ, Wilkie D, Woodham RH. Nuclear magnetic resonance studies of blood plasma and urine from subjects with chronic renal failure: identification of trimethylamine-N-oxide. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 1991;1096(2):101-7. [DOI:10.1016/0925-4439(91)90046-C]
17. Mackay RJ, McEntyre CJ, Henderson C, Lever M, George PM. Trimethylaminuria: causes and diagnosis of a socially distressing condition. The Clinical Biochemist Reviews. 2011;32(1):33.
18. Koukouritaki SB, Poch MT, Henderson MC, Siddens LK, Krueger SK, VanDyke JE, et al. Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants. Journal of Pharmacology and Experimental Therapeutics. 2007;320(1):266-73. [DOI:10.1124/jpet.106.112268] [PMID]
19. Phillips IR, Shephard EA. Drug metabolism by flavin-containing monooxygenases of human and mouse. Expert opinion on drug metabolism & toxicology. 2017;13(2):167-81. [DOI:10.1080/17425255.2017.1239718] [PMID]
20. Galavi H, Mollashahee‐Kohkan F, Saravani R, Sargazi S, Noorzehi N, Shahraki H. HHEX gene polymorphisms and type 2 diabetes mellitus: A case‐control report from Iran. Journal of cellular biochemistry. 2019;120(10):16445-51. [DOI:10.1002/jcb.28788] [PMID]
21. Galavi H, Noorzehi N, Saravani R, Sargazi S, Mollashahee-Kohkan F, Shahraki H. Association study of SREBF-2 gene polymorphisms and the risk of type 2 diabetes in a sample of Iranian population. Gene. 2018;660:145-50. [DOI:10.1016/j.gene.2018.03.080] [PMID]
22. Li W, Zhu L, Huang H, He Y, Lv J, Li W, et al. Identification of susceptible genes for complex chronic diseases based on disease risk functional SNPs and interaction networks. Journal of Biomedical Informatics. 2017;74:137-44. [DOI:10.1016/j.jbi.2017.09.006] [PMID]
23. Loktionov A. Common gene polymorphisms and nutrition: emerging links with pathogenesis of multifactorial chronic diseases. The Journal of nutritional biochemistry. 2003;14(8):426-51. [DOI:10.1016/S0955-2863(03)00032-9] [PMID]
24. Damtie S, Biadgo B, Baynes HW, Ambachew S, Melak T, Asmelash D, et al. Chronic kidney disease and associated risk factors assessment among diabetes mellitus patients at a tertiary hospital, Northwest Ethiopia. Ethiopian journal of health sciences. 2018;28(6). [DOI:10.4314/ejhs.v28i6.3] [PMID] [PMCID]
25. Pagels AA, Söderkvist BK, Medin C, Hylander B, Heiwe S. Health-related quality of life in different stages of chronic kidney disease and at initiation of dialysis treatment. Health and quality of life outcomes. 2012;10(1):1-11. [DOI:10.1186/1477-7525-10-71] [PMID] [PMCID]
26. Florkowski CM, Chew-Harris JS. Methods of estimating GFR-different equations including CKD-EPI. The Clinical Biochemist Reviews. 2011;32(2):75.
27. MWer S, Dykes D, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic acids res. 1988;16(3):1215. [DOI:10.1093/nar/16.3.1215] [PMID] [PMCID]
28. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2):263-5. [DOI:10.1093/bioinformatics/bth457] [PMID]
29. Phillips IR, Shephard EA. Flavin-containing monooxygenase 3 (FMO3): genetic variants and their consequences for drug metabolism and disease. Xenobiotica. 2020;50(1):19-33. [DOI:10.1080/00498254.2019.1643515] [PMID]
30. Shephard EA, Treacy EP, Phillips IR. Clinical utility gene card for: Trimethylaminuria-update 2014. Eur J Hum Genet. 2015;23(9):1269. https://doi.org/10.1038/ejhg.2014.226 [DOI:10.1038/ejhg.2014.254] [PMID] [PMCID]
31. Wei H, Zhao M, Huang M, Li C, Gao J, Yu T, et al. FMO3-TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction: evidence from an Asian population. Frontiers of medicine. 2021:1-11. [DOI:10.1007/s11684-021-0857-2] [PMID]
32. Shan Z, Sun T, Huang H, Chen S, Chen L, Luo C, et al. Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. The American journal of clinical nutrition. 2017;106(3):888-94. [DOI:10.3945/ajcn.117.157107] [PMID]
33. Hernandez D, Janmohamed A, Chandan P, Phillips IR, Shephard EA. Organization and evolution of the flavin-containing monooxygenase genes of human and mouse: identification of novel gene and pseudogene clusters. Pharmacogenetics and Genomics. 2004;14(2):117-30. [DOI:10.1097/00008571-200402000-00006] [PMID]
34. Dolphin CT, Janmohamed A, Smith RL, Shephard EA. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nature genetics. 1997;17(4):491-4. [DOI:10.1038/ng1297-491] [PMID]
35. Teft WA, Morse BL, Leake BF, Wilson A, Mansell SE, Hegele RA, et al. Identification and characterization of trimethylamine-N-oxide uptake and efflux transporters. Molecular pharmaceutics. 2017;14(1):310-8. [DOI:10.1021/acs.molpharmaceut.6b00937] [PMID] [PMCID]
36. Shih DM, Wang Z, Lee R, Meng Y, Che N, Charugundla S, et al. Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis [S]. Journal of lipid research. 2015;56(1):22-37. [DOI:10.1194/jlr.M051680] [PMID] [PMCID]
37. Allerston CK, Shimizu M, Fujieda M, Shephard EA, Yamazaki H, Phillips IR. Molecular evolution and balancing selection in the flavin-containing monooxygenase 3 gene (FMO3). Pharmacogenetics and genomics. 2007;17(10):827-39. [DOI:10.1097/FPC.0b013e328256b198] [PMID]
38. Warrier M, Shih DM, Burrows AC, Ferguson D, Gromovsky AD, Brown AL, et al. The TMAO-generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance. Cell reports. 2015;10(3):326-38. [DOI:10.1016/j.celrep.2014.12.036] [PMID] [PMCID]

Add your comments about this article : Your username or Email:

Send email to the article author

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2015 All Rights Reserved | Reports of Biochemistry and Molecular Biology

Designed & Developed by : Yektaweb