Abstract
An increasing body of evidence has shown that the amino acid changes at position 1298 might eliminate methylenetetrahydrofolate reductase (MTHFR) enzyme activity, leading to insufficient folic acid and subsequent human chromosome breakage. Epidemiological studies have linked MTHFR single-nucleotide polymorphism (SNP) rs1801131 to myeloid leukemia risk, with considerable discrepancy in their results. We therefore were prompted to clarify this issue by use of a meta-analysis. The search terms were used to cover the possible reports in the MEDLINE, Web of Knowledge, and China National Knowledge Infrastructure (CNKI) databases. Odds ratios were estimated to assess the association of SNP rs1801131 with myeloid leukemia risk. Statistical heterogeneity was detected using the Q-statistic and I 2 metric. Subgroup analysis was performed by ethnicity, histological subtype, and Hardy-Weinberg equilibrium (HWE). This meta-analysis of eight publications with a total of 1,114 cases and 3,227 controls revealed no global association. Nor did the subgroup analysis according to histological subtype and HWE show any significant associations. However, Asian individuals who harbored the CC genotype were found to have 1.66-fold higher risk of myeloid leukemia (odds ratio, 1.66; 95 % confidence interval, 1.10 to 2.49; P h = 0.342; I 2 = 0.114). Our meta-analysis has presented evidence supporting a possible association between the CC genotype of MTHFR SNP rs1801131 and myeloid leukemia in Asian populations.
Similar content being viewed by others
References
Bloomfield CD, Caligiury M. Molecular biology of leukemias. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 2389–404.
Rowley JD. The critical role of chromosome translocations in human leukemias. Annu Rev Genet. 1998;32:495–519.
Pui CH. Childhood leukaemias. 2nd ed. Cambridge: Cambridge University Press; 2006.
Gabert J et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe Against Cancer program. Leukemia. 2003;17(12):2318–57.
Smith MT, Zhang L. Biomarkers of leukemia risk: benzene as a model. Environ Health Perspect. 1998;106 Suppl 4:937–46.
Robien K, Ulrich CM. 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Am J Epidemiol. 2003;157(7):571–82.
Blount BC et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A. 1997;94(7):3290–5.
Duthie SJ et al. Impact of folate deficiency on DNA stability. J Nutr. 2002;132(8 Suppl):2444S–9S.
Franco RF et al. A second mutation in the methylenetetrahydrofolate reductase gene and the risk of venous thrombotic disease. Br J Haematol. 1999;105(2):556–9.
Goyette P et al. Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet. 1994;7(4):551.
Frosst P et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111–3.
Weisberg I et al. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64(3):169–72.
Skibola CF et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci U S A. 1999;96(22):12810–5.
da Costa Ramos FJ et al. Association between the MTHFR A1298C polymorphism and increased risk of acute myeloid leukemia in Brazilian children. Leuk Lymphoma. 2006;47(10):2070–5.
Hur M et al. Methylenetetrahydrofolate reductase A1298C genotypes are associated with the risks of acute lymphoblastic leukaemia and chronic myelogenous leukaemia in the Korean population. Clin Lab Haematol. 2006;28(3):154–9.
Moon HW et al. MTHFR 677CC/1298CC genotypes are highly associated with chronic myelogenous leukemia: a case–control study in Korea. Leuk Res. 2007;31(9):1213–7.
Higgins JP et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719–48.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.
Egger M et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–34.
Lightfoot TJ et al. Genetic variation in the folate metabolic pathway and risk of childhood leukemia. Blood. 2010;115(19):3923–9.
Lordelo GS et al. Association between methylenetetrahydrofolate reductase and glutathione S-transferase M1 gene polymorphisms and chronic myeloid leukemia in a Brazilian population. Genet Mol Res. 2012;11(2):1013–26.
Zheng MM et al. Association of single nucleotide polymorphism of methylenetetrahydrofolate reductase gene with susceptibility to acute leukemia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2013;30(4):451–5.
Khorshied MM et al. Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms in chronic myeloid leukemia: an Egyptian study. Med Oncol. 2014;31(1):794.
Zintzaras E, Lau J. Trends in meta-analysis of genetic association studies. J Hum Genet. 2008;53(1):1–9.
Cheson BD. The chronic lymphocytic leukemias. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 2447–65.
Kantarjian HM, Faderl S, Talpaz M. Chronic myelogenous leukemia. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 2433–47.
Weinstein HJ, Tarbell N. Leukemias and lymphomas of childhood. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 2235–56.
van der Put NM et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998;62(5):1044–51.
Wang H et al. Methylenetetrahydrofolate reductase polymorphism C677T is a protective factor for pediatric acute lymphoblastic leukemia in the Chinese population: a meta-analysis. Genet Test Mol Biomark. 2012;16(12):1401–7.
Yan J et al. A meta-analysis of MTHFR C677T and A1298C polymorphisms and risk of acute lymphoblastic leukemia in children. Pediatr Blood Cancer. 2012;58(4):513–8.
Cole P, Rodu B. Descriptive epidemiology: cancer statistics. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles and practice of oncology. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 228–41.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dong, S., Liu, Y. & Chen, J. MTHFR gene polymorphism and risk of myeloid leukemia: a meta-analysis. Tumor Biol. 35, 8913–8919 (2014). https://doi.org/10.1007/s13277-014-2082-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-014-2082-y