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Abstract - Association between A1298C and C677T methylenetetrahydrofolate reductase gene polymorphisms and the risk of acute lymphoid and myeloid leukemia
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Yousef Mortazavi, Zahra Ghasemi, Sanaz Aghajani, Mohammad Eftekhari Shirkohy, Minoosh Moghimi, Alireza Khademolmelleh, Saeideh Mazloomzadeh


Background: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism, DNA methylation and synthesis. Two MTHFR polymorphisms, C677T and A1298C, have been associated with reduced enzyme activity. Rapidly replicating cell types, such as hematopoietic cells, may be especially sensitive to changes in the availability of intracellular folate. The aim of this case-control study was to evaluate whether  the  mentioned polymorphisms in MTHFR gene plays a role in altering susceptibility to acute myeloid leukemia and acute lymphoblastic leukemia.

Material and methods: 281 patients comprising 101 patients with acute lymphoblastic leukemia and 180 patients with acute myeloid leukemia as well as 490 normal individuals as control group were studied for the C677T and the A1298C MTHFR gene polymorphisms using PCR. The PCR products were digested with HinfI and Mbo‌‌‌‌‌II restriction enzymes respectively (RFLP). The results were electrophoresed on agaros gel and analyzed using SPSS software.

Results: The number of patients with acute lymphoblastic leukemia who had C677T polymorphism was less than the control group, but this difference was not significant. Also, combination of C677T/A1298C genotypes in both case and control groups, showed no increase of susceptibility to acute myeloid leukemia and/or acute lymphoblastic leukemia risk. There was no significant relationship between common MTHFR variants and the risk of acute myeloid leukemia and acute lymphoblastic leukemia in controls and the cases.

Conclusion: Our findings showed that the MTHFR C677T and A1298C gene variants do not have a major influence on the susceptibility to acute lymphoblastic leukemia and acute myeloid leukemia in Iranian individuals. However, the C677T polymorphism has a protection role in acute lymphoblastic leukemia group, but this difference was not statistically significant.

Key words: MTHFR, polymorphism, acute lymphoblastic leukemia, acute myeloid leukemia, PCR/RFLP

Corresponding author: Dr. Yousef Mortazavi, Department of Pathology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran. Post code: 45139 56111. Tel: +98 912 389 2427. E-mail: youmort@yahoo.com



1. Diab NA, Elderdery AY, Mills J, Khalil HB. The role of genetic polymorphisms of the MTHFR (C677T and A1298C) gene in the incidence of Acute Myeloid Leukaemia. Pakistani Journal of Medical and Health Sciences. 2019; 13(4):1330-4.

2. Qin Y-T, Zhang Y, Wu F, Su Y, Lu G-N, Wang R-S. Association between MTHFR polymorphisms and acute myeloid leukemia risk: a meta-analysis. PloS one. 2014; 9(2).

3. Parsa N. Environmental factors inducing human cancers. Iranian journal of public health. 2012; 41(11):1.

4. Nichol JN, Kinal M, Miller WH. The etiology of acute leukemia. Neoplastic Diseases of the Blood: Springer. 2018; 161-77. https://doi.org/10.1007/978-3-319-64263-5_12

5. Hansen B-A, Wendelbo Ø, Bruserud Ø, Hemsing AL, Mosevoll KA, Reikvam H. Sepsis in acute leukemia; epidemiology; pathophysiology, etiology and treatment. Mediterranean Journal of Hematology and Infectious Diseases. 2020; 12(1):e2020009-e.https://doi.org/10.4084/mjhid.2020.009

6. Abdelhalim DA, Elgamal BM, ElKafoury MR, Hassan NM, Hussein MM, Elhefnawi MM, et al. MicroRNA-150 down regulation in acute myeloid leukaemia patients and its prognostic implication. Open access Macedonian journal of medical sciences. 2018; 6(11):1993. https://doi.org/10.3889/oamjms.2018.420

7. Naushad S, Dorababu P, Digumarti R. Genetic variants of folate metabolic pathways in hematological toxicity of leukemia patients. Handbook of nutrition and diet in leukemia and blood disease therapy: Wageningen Academic Publishers. 2016; 291-302. https://doi.org/10.3920/978-90-8686-822-3_17

8. Liu P, Zhang M, Xie X, Jin J, Holman CDAJ. Polymorphisms of 5, 10-methylenetetrahydrofolate reductase and thymidylate synthase, dietary folate intake, and the risk of leukemia in adults. Tumor Biology. 2016; 37(3):3265-75. https://doi.org/10.1007/s13277-015-4168-6

9. Kuo C, Cheng C, Kuo H, Chen C, Huang C. Genetic Polymorphisms of One-carbon Enzymes Interactively Modify Metabolic Folate Stress and Risks of Hepatocellular Carcinoma Development. J Nutr Food Sci. 2016; 6(518):2. https://doi.org/10.4172/2155-9600.1000518

10. Wang D, Bai L, Zhai Q, Li Y, Cao M, Hai J, et al. Association of MTHFR C677T and A1298C polymorphisms with the development of type 2 diabetic nephropathy and their interaction with environmental factors. Int J Clin Exp Pathol. 2017; 10(3):3778-85.

11. Zhang S, Jiang J, Tang W, Liu L. Methylenetetrahydrofolate reductase C677T (Ala>Val, rs1801133 C>T) polymorphism decreases the susceptibility of hepatocellular carcinoma: a meta-analysis involving 12,628 subjects. Bioscience reports. 2020; 40(2). https://doi.org/10.1042/BSR20194229

12. Garcia-Hernandez SC, Meneses-Sanchez P, Porchia LM, Torres-Rasgado E, Pérez-Fuentes R, Gonzalez-Mejia ME. Differential effects of the methylenetetrahydrofolate reductase polymorphisms (C677T and A1298C) on hematological malignancies among Latinos: a meta-analysis. Genetics and Molecular Biology. 2019; 42(3):549-59. https://doi.org/10.1590/1678-4685-gmb-2018-0161

13. Zhang B, Zhang W, Yan L, Wang D. The association between MTHFR gene C677T polymorphism and ALL risk based on a meta-analysis involving 17,469 subjects. Clinica chimica acta; international journal of clinical chemistry. 2017; 466:85-92. https://doi.org/10.1016/j.cca.2017.01.001

14. Şahin TG, Sayal B, Coşgun E, Besler T, Beksaç S. Methylenetetrahydrofolate reductase enzyme mutations and relationship of homocysteine Vitamin B12 and folate blood levels. Gynecology Obstetrics & Reproductive Medicine. 2016; 19(1):1-6.

15. Garcia-Hernandez SC, Meneses-Sanchez P, Porchia LM, Torres-Rasgado E, Perez-Fuentes R, Gonzalez-Mejia ME. Differential effects of the methylenetetrahydrofolate reductase polymorphisms (C677T and A1298C) on hematological malignancies among Latinos: a meta-analysis. Genet Mol Biol. 2019; 42(3):549-59. https://doi.org/10.1590/1678-4685-gmb-2018-0161

16. Kaluzna EM, Strauss E, Swiatek-Koscielna B, Zajac-Spychala O, Gowin E, Nowak JS, et al. The methylenetetrahydrofolate reductase 677T-1298C haplotype is a risk factor for acute lymphoblastic leukemia in children. Medicine. 2017; 96(51):e9290. https://doi.org/10.1097/MD.0000000000009290

17. Akin DF, Oner DA, Sipahi K, Mumcuoglu M, Kurekci E, Ezer U, et al. Screening of polymorphisms in the folate pathway in Turkish pediatric Acute Lymphoblastic Leukemia patients. Egyptian Journal of Medical Human Genetics. 2017; 18(4):349-53. https://doi.org/10.1016/j.ejmhg.2017.03.003

18. Lien S-YA, Young L, Gau B-S, Shiao SPK. Meta-prediction of MTHFR gene polymorphism-mutations, air pollution, and risks of leukemia among world populations. Oncotarget. 2017; 8(3):4387. https://doi.org/10.18632/oncotarget.13876

19. Frikha R, Bouayed N, Ben Rhouma B, Keskes L, Rebai T. A duplex polymerase chain reaction‐restriction fragment length polymorphism for rapid screening of methylenetetrahydrofolate reductase gene variants: Genotyping in acute leukemia. Journal of clinical laboratory analysis. 2018; 32(1):e22198. https://doi.org/10.1002/jcla.22198

20. Lv H, Hu SY, Du ZZ, Zhai Z, Cao L, Sun YN, et al. Gene polymorphisms in the folate metabolic pathway and risk of pediatric acute lymphoblastic leukemia: a case-control study in a Chinese population. Int J Clin Exp Pathol. 2018; 11(3):1724-31.

21. Hiraoka M, Kagawa Y. Genetic polymorphisms and folate status. Congenital anomalies. 2017; 57(5):142-9. https://doi.org/10.1111/cga.12232

22. Zhang L, Yin RX, Liu WY, Miao L, Wu DF, Aung LH, et al. Association of methylenetetrahydrofolate reductase C677T polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Lipids in health and disease. 2010; 9:123.

23. Eloualid A, Abidi O, Charif M, El Houate B, Benrahma H, Louanjli N, et al. Association of the MTHFR A1298C variant with unexplained severe male infertility. PLoS One. 2012; 7(3):e34111.

24. Long S, Goldblatt J. MTHFR genetic testing: Controversy and clinical implications. Australian family physician. 2016; 45(4):237-40.

25. Huang L, Deng D, Peng Z, Ye F, Xiao Q, Zhang B, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) are associated with susceptibility to adult acute myeloid leukemia in a Chinese population. Cancer epidemiology. 2015; 39(3):328-33.

26. Schnakenberg E, Mehles A, Cario G, Rehe K, Seidemann K, Schlegelberger B, et al. Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population. BMC medical genetics. 2005; 6:23.

27. Balta G, Yuksek N, Ozyurek E, Ertem U, Hicsonmez G, Altay C, et al. Characterization of MTHFR, GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes in childhood acute leukemia. American journal of hematology. 2003; 73(3):154-60. https://doi.org/10.1002/ajh.10339

28. Alcasabas P, Ravindranath Y, Goyette G, Haller A, Del Rosario L, Lesaca-Medina MY, et al. 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the risk of acute lymphoblastic leukemia (ALL) in Filipino children. Pediatric blood & cancer. 2008; 51(2):178-82.

29. Krajinovic M, Lamothe Sp, Labuda D, Lemieux-Blanchard Em, Théorêt Y, Moghrabi A, et al. Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Blood. 2004; 103(1):252-7. https://doi.org/10.1182/blood-2003-06-1794

30. Ramirez-Pacheco A, Moreno-Guerrero S, Alamillo I, Medina-Sanson A, Lopez B, Moreno-Galvan M. Mexican Childhood Acute Lymphoblastic Leukemia: A Pilot Study of the MDR1 and MTHFR Gene Polymorphisms and Their Associations with Clinical Outcomes. Genetic testing and molecular biomarkers. 2016; 20(10):597-602. https://doi.org/10.1089/gtmb.2015.0287

31. Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proceedings of the National Academy of Sciences of the United States of America. 1999; 96(22):12810-5. https://doi.org/10.1073/pnas.96.22.12810

32. Pereira TV, Rudnicki M, Pereira AC, Pombo-de-Oliveira MS, Franco RF. 5, 10-Methylenetetrahydrofolate reductase polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis. Cancer Epidemiology and Prevention Biomarkers. 2006; 15(10):1956-63. https://doi.org/10.1158/1055-9965.EPI-06-0334

33. Schnakenberg E, Mehles A, Cario G, Rehe K, Seidemann K, Schlegelberger B, et al. Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population. BMC medical genetics. 2005; 6(1):23. https://doi.org/10.1186/1471-2350-6-23

34. Pufulete M, Al-Ghnaniem R, Leather AJ, Appleby P, Gout S, Terry C, et al. Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology. 2003; 124(5):1240-8. https://doi.org/10.1016/S0016-5085(03)00279-8

35. Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, Greaves MF, et al. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proceedings of the National Academy of Sciences. 2001; 98(7):4004-9. https://doi.org/10.1073/pnas.061408298

36. Pieroth R, Paver S, Day S, Lammersfeld C. Folate and its impact on cancer risk. Current nutrition reports. 2018; 7(3):70-84. https://doi.org/10.1007/s13668-018-0237-y


Volume 4, Number 58 (2020)