Review Article

Association of MTHFR C677T and A1298C Polymorphisms with Susceptibility to Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis


Background: The relation between methylenetetrahydrofolate reductase)MTHFR( polymorphisms and the risk of developing Chronic lymphocytic leukemia (CLL) is not still clear, while there are reports about the association of MTHFR  C677T and A1298C polymorphisms with developing CLL, there are other reports that rolled out the association of MTHFR polymorphisms with developing CLL. Therefore herein we carried out this meta-analysis to clear the association of MTHFR polymorphisms with the risk of CLL,

Methods: A comprehensive search was performed through PubMed, Scopus and Embase from inception to Aug 2020. Odds ratios (OR) with their corresponding 95% confidence intervals (CI) for five possible genetic models were calculated. Heterogeneity was evaluated using the Cochran Q test and the I2 statistic.

Results: Totals of 1290 cases and 1887 controls for the C677T polymorphism and 1117 cases and 1256 controls for the A1298C polymorphism were included in our analysis. Analyzing the MTHFR C677T and A1298C polymorphisms genotypes showed an association between MTHFR polymorphism at A1298C under Allelic model and the risk of CLL (OR = 1.12, 95% CI = 1.01–1.25), however there was no association between MTHFR polymorphism at MTHFR C677T and risk of CLL.

Conclusion: The risk of developing CLL might be associated with MTHFR polymorphism at A1298C under allelic model and not associated with MTHFR polymorphisms at C677T, However, further studies considering other factors such as age, gender, ethnicity, gene-gene interaction and environmental condition are needed to clear the true association of MTHFR polymorphisms with CLL.

1. Siegel RL, Miller KD, Jemal A (2019). Cancer statistics, 2019. CA Cancer J Clin, 69:7-34.
2. Hallek M (2019). Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment. Am J Hematol, 94(11):1266-1287.
3. Berndt SI, Camp NJ, Skibola CF, et al (2016). Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia. Nat Commun, 7:10933.
4. Oancea SC, Rundquist BC, Simon I, et al (2017). County level incidence rates of chronic lymphocytic leukemia are associated with residential radon levels. Future Oncol, 13(21):1873-1881.
5. Karakosta M, Delicha E-M, Kouraklis G, Manola KN (2016). Association of various risk factors with chronic lymphocytic leukemia and its cytogenetic characteristics. Arch Environ Occup Health, 71(6):317-329.
6. Zhou Y, Lu H, Yang M, Xu C (2019). Adverse drug events associated with ibrutinib for the treatment of elderly patients with chronic lymphocytic leukemia: A systematic review and meta-analysis of randomized trials. Medicine (Baltimore), 98(33):e16915.
7. Elmore CL, Wu X, Leclerc D, et al (2007). Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase. Mol Genet Metab, 91(1):85-97.
8. Umay A, Bilgin R, Akgöllü E, Gürkan E, Kis C (2018). Relationship between MTHFR gene polymorphisms (C677T and A1298C) and chronic lymphocytic leukemia in the Turkish population. Meta Gene, 17:232-236.
9. Zingg J-M, Jones PA (1997). Genetic and epigenetic aspects of DNA methylation on genome expression, evolution, mutation and carcinogenesis. Carcinogenesis, 18(5):869-82.
10. Hussain SR, Naqvi H, Raza ST, et al (2012). Methylenetetrahydrofolate reductase C677T genetic polymorphisms and risk of leukaemia among the North Indian population. Cancer Epidemiol, 36(4):e227-31.
11. Reis AAdS, de Alcântara KC, de Farias DLC, et al (2019). The influence of MTHFR C677T polymorphism in chronic lymphocytic leukemia. Electrophoresis, 40(12-13):1715-1718 .
12. Abyadeh M, Heydarinejad F, Khakpash M, et al (2020). Association of Apolipoprotein E gene polymorphism with Preeclampsia: a meta-analysis. Hypertens Pregnancy, 39(2):196-202.
13. Peterson J, Welch V, Losos M, Tugwell P (2011). The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Hospital Research Institute.
14. Wigginton JE, Cutler DJ, Abecasis GR (2005). A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet, 76(5): 887–893.
15. Huedo-Medina TB, Sánchez-Meca J, Marín-Martínez F, Botella J (2006). Assessing heterogeneity in meta-analysis: Q statistic or I² index? Psychol Methods, 11(2):193-206.
16. DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Control Clin Trials, 7(3):177-88.
17. Abyadeh M, Djafarian K, Heydarinejad F, et al (2019). Association between Apolipoprotein E Gene Polymorphism and Alzheimer's Disease in an Iranian Population: A Meta-Analysis. J Mol Neurosci, 69(4):557-562.
18. Asefi Y, Gohari Mahmoudabad A, Habibian Sezavar A, et al (2020). Association between maternal cadmium exposure and preterm birth: a meta-analysis. Int J Environ Health Res:1-10.
19. Egger M, Smith GD, Schneider M, Minder C (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315(7109): 629–634.
20. Rakonjac N, Ilić V, Šupić G, Cikota B, et al (2008). C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene in patients with chronic lymphocytic leukemia and diffuse large B cell lymphoma. Serbian Journal of Experimental and Clinical Research, 9(1):9-12.
21. Gonzalez Ordonez A, FernAandez J, Alvarez CF, et al (2000). Normal frequencies of the C677T genotypes on the methylenetetrahydrofolate reductase (MTHFR) gene among lymphoproliferative disorders but not in multiple myeloma. Leuk Lymphoma, 39:607-12.
22. Nückel H, Frey U, Dürig J, Dührsen U, Siffert W (2004). Methylenetetrahydrofolate reductase (MTHFR) gene 677C> T and 1298A> C polymorphisms are associated with differential apoptosis of leukemic B cells in vitro and disease progression in chronic lymphocytic leukemia. Leukemia, 18(11):1816-23.
23. Rudd MF, Sellick GS, Allinson R, et al (2004). MTHFR polymorphisms and risk of chronic lymphocytic leukemia. Cancer Epidemiol Biomarkers Prev, 13(12):2268-70.
24. Gra OA, Glotov AS, Nikitin EA, et al (2008). Polymorphisms in xenobiotic‐metabolizing genes and the risk of chronic lymphocytic leukemia and non‐Hodgkin's lymphoma in adult Russian patients. Am J Hematol, 83(4):279-87.
25. Gong J-M, Shen Y, Shan W-W, He Y-X (2018). The association between MTHFR polymorphism and cervical cancer. Sci Rep, 8:7244.
26. Chen J, Gammon MD, Chan W, et al (2005). One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer Res, 65(4):1606-14.
27. Kennedy DA, Stern SJ, Matok I, et al (2012). Folate intake, MTHFR polymorphisms, and the risk of colorectal cancer: a systematic review and meta-analysis. J Cancer Epidemiol, 2012:952508.
28. He L, Shen Y (2017). MTHFR C677T polymorphism and breast, ovarian cancer risk: a meta-analysis of 19,260 patients and 26,364 controls. Onco Targets Ther, 10:227.
29. Kumar P, Rai V (2018). MTHFR C677T polymorphism and risk of esophageal cancer: An updated meta-analysis. Egyptian Journal of Medical Human Genetics, 19:273-284.
30. Liu W, Li Y, Li R, et al (2016). Association of MTHFR A1298C polymorphism with breast cancer and/or ovarian cancer risk: an updated meta-analysis. Afr J Tradit Complement Altern Med, 13(5):72-86.
31. Tong W, Tong G, Jin D, Lv Q (2018). MTHFR C677T and A1298C polymorphisms and lung cancer risk in a female Chinese population. Cancer Manag Res, 10: 4155–4161.
IssueVol 50 No 1 (2021) QRcode
SectionReview Article(s)
Methylenetetrahydrofolate reductase gene Meta-analysis Chronic lymphocytic leukemia Polymorphism

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RAOUFI A, RAHIMI KELARIJANI B, AHADI HR, HASSANI DERAKHSHANDEH B, NOOROOLLAHZADEH Z, HAJIFATHALI A. Association of MTHFR C677T and A1298C Polymorphisms with Susceptibility to Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis. Iran J Public Health. 50(1):83-92.