- Volume 14 Issue 11
DOI QR Code
The MTHFR C677T Polymorphism and Risk of Acute Lymphoblastic Leukemia: an Updated Meta-analysis Based on 37 Case-control Studies
- Jiang, Yuan (Lab of Molecular Genetics of Aging & Tumor, Faculty of Life Science and Technology, Kunming University of Science and Technology) ;
- Hou, Jing (Lab of Molecular Genetics of Aging & Tumor, Faculty of Life Science and Technology, Kunming University of Science and Technology) ;
- Zhang, Qiang (Lab of Molecular Genetics of Aging & Tumor, Faculty of Life Science and Technology, Kunming University of Science and Technology) ;
- Jia, Shu-Ting (Lab of Molecular Genetics of Aging & Tumor, Medical Faculty, Kunming University of Science and Technology) ;
- Wang, Bo-Yuan (Lab of Molecular Genetics of Aging & Tumor, Faculty of Life Science and Technology & Faculty of Environmental Science and Engineering, Kunming University of Science and Technology) ;
- Zhang, Ji-Hong (Lab of Molecular Genetics of Aging & Tumor, Medical Faculty, Kunming University of Science and Technology) ;
- Tang, Wen-Ru (Lab of Molecular Genetics of Aging & Tumor, Medical Faculty, Kunming University of Science and Technology) ;
- Luo, Ying (Lab of Molecular Genetics of Aging & Tumor, Medical Faculty, Kunming University of Science and Technology)
- Published : 2013.11.30
Background: The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) has been associated with acute lymphoblastic leukemia (ALL). However, results were conflicting. The aim of this study was to quantitatively summarize the evidence for the MTHFRC677T polymorphism and ALL risk. Methods: Electronic searches of PubMed and the Chinese Biomedicine database were conducted to select case-control studies containing available genotype frequencies of C677T and the odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of any association. Results: Case-control studies including 6,371 cases and 10,850 controls were identified. The meta-analysis stratified by ethnicity showed that individuals with the homozygous TT genotype had decreased risk of ALL (OR= 0.776, 95% CI: 0.687~0.877, p< 0.001) in Caucasians (OR= 0.715, 95% CI: 0.655~0.781, p= 0.000). However, results among Asians (OR=0.711, 95% CI: 0.591~1.005, p= 0.055) and others (OR=0.913, 95% CI: 0.656~1.271, p= 0. 590) did not suggest an association. A symmetric funnel plot, the Egger's test (P=0.093), and the Begg- test (P=0.072) were all suggestive of the lack of publication bias. Conclusion: This meta-analysis supports the idea that the MTHFR C677T genotype is associated with risk of ALL in Caucasians. To draw comprehensive and true conclusions, further prospective studies with larger numbers of participants worldwide are needed to examine associations between the MTHFRC677T polymorphism and ALL.
MTHFR C677T;meta-analysis;acute lymphoblastic leukemia;risk factor
- Alcasabas P, Ravindranath Y, Goyette G, et al (2008). 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the risk of acute lymphoblastic leukemia (ALL) in Filipino children. Pediatr Blood Cancer, 51, 178-82. https://doi.org/10.1002/pbc.21511
- Azhar MR, Rahimi Z, Vaisi-Raygani A, et al (2012). Lack of association between MTHFR C677T and A1298C polymorphisms and risk of childhood acute lymphoblastic leukemia in the Kurdish population from Western Iran. Genet Test Mol Biomarkers, 16, 198-202. https://doi.org/10.1089/gtmb.2011.0041
- Bailey LB, Gregory JF, 3rd (1999). Folate metabolism and requirements. J Nutr, 129, 779-82. https://doi.org/10.1093/jn/129.4.779
- Balta G, Yuksek N, Ozyurek E, et al (2003). Characterization of MTHFR, GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes in childhood acute leukemia. Am J Hematol, 73, 154-60. https://doi.org/10.1002/ajh.10339
- Chan JY, Ugrasena DG, Lum DW, et al (2011). Xenobiotic and folate pathway gene polymorphisms and risk of childhood acute lymphoblastic leukaemia in Javanese children. Hematol Oncol, 29, 116-23. https://doi.org/10.1002/hon.965
- Chatzidakis K, Goulas A, Athanassiadou-Piperopoulou F, et al (2006). Methylenetetrahydrofolate reductase C677T polymorphism: association with risk for childhood acute lymphoblastic leukemia and response during the initial phase of chemotherapy in greek patients. Pediatr Blood Cancer, 47, 147-51. https://doi.org/10.1002/pbc.20574
- Damnjanovic T, Milicevic R, Novkovic T, et al (2010). Association between the methylenetetrahydrofolate reductase polymorphisms and risk of acute lymphoblastic leukemia in Serbian children. J Pediatr Hematol Oncol, 32, e148-50. https://doi.org/10.1097/MPH.0b013e3181cbd252
- de Jonge R, Tissing WJ, Hooijberg JH, et al (2009). Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood, 113, 2284-9. https://doi.org/10.1182/blood-2008-07-165928
- Deligezer U, Akisik E, Dalay N (2003). Genotyping of the MTHFR gene polymorphism, C677T in patients with leukemia by melting curve analysis. Mol Diagn, 7, 181-5. https://doi.org/10.1007/BF03260036
- DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Control Clin Trials, 7, 177-88. https://doi.org/10.1016/0197-2456(86)90046-2
- Egger M, Davey Smith G, Schneider M, Minder C (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315, 629-34. https://doi.org/10.1136/bmj.315.7109.629
- Franco RF, Simoes BP, Tone LG, et al (2001). The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukaemia. Br J Haematol, 115, 616-8. https://doi.org/10.1046/j.1365-2141.2001.03140.x
- Frosst P, Blom HJ, Milos R, et al (1995). A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet, 10, 111-3. https://doi.org/10.1038/ng0595-111
- Gemmati D, Ongaro A, Scapoli G L, et al (2004). Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin’s lymphoma in adults. Cancer Epidemiol Biomarkers Prev, 13, 787-94.
- Giovannetti E, Ugrasena DG, Supriyadi E, et al (2008). Methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase promoter (TSER) polymorphisms in Indonesian children with and without leukemia. Leuk Res, 32, 19-24. https://doi.org/10.1016/j.leukres.2007.02.011
- Golbahar J, Aminzadeh MA, Sharifkazemi MB, Rezaian GR (2005). Association of red blood cell 5-methyltetrahydrofolate and severity of coronary artery disease: a cross-sectional study from Shiraz, southern Iran. Heart Vessels, 20, 203-6. https://doi.org/10.1007/s00380-004-0823-3
- Govindaiah V, Naushad SM, Prabhakara K, et al (2009). Association of parental hyperhomocysteinemia and C677T Methylene tetrahydrofolate reductase (MTHFR) polymorphism with recurrent pregnancy loss. Clin Biochem, 42, 380-6. https://doi.org/10.1016/j.clinbiochem.2008.12.003
- Jiang H, Gu LJ, Xue HL (2004). Methylenetetrahydrofolate reductase gene polymorphism of childhood acute lymphocytic leukaemia. Zhonghua Xue Ye Xue Za Zhi, 25, 439-40.
- Jilma B, Kamath S, and Lip GY (2003). ABC of antithrombotic therapy: Antithrombotic therapy in special circumstances. II-In children, thrombophilia, and miscellaneous conditions. BMJ, 326, 93-6.
- Kamel AM, Moussa HS, Ebid GT, et al (2007). Synergistic effect of methyltetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphism as risk modifiers of pediatric acute lymphoblastic leukemia. J Egypt Natl Canc Inst, 19, 96-105.
- Kantar M, Kosova B, Cetingul N, et al (2009). Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms and therapy-related toxicity in children treated for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Leuk Lymphoma, 50, 912-7. https://doi.org/10.1080/10428190902893819
- Karathanasis NV, Stiakaki E, Goulielmos GN, and Kalmanti M (2011). The role of the methylenetetrahydrofolate reductase 677 and 1298 polymorphisms in Cretan children with acute lymphoblastic leukemia. Genet Test Mol Biomarkers, 15, 5-10. https://doi.org/10.1089/gtmb.2010.0083
- Kim HN, Kim YK, Lee IK, et al (2009). Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies. Leuk Res, 33, 82-7. https://doi.org/10.1016/j.leukres.2008.07.026
- Kim NK, Chong SY, Jang MJ, et al (2006). Association of the methylenetetrahydrofolate reductase polymorphism in Korean patients with childhood acute lymphoblastic leukemia. Anticancer Res, 26, 2879-81.
- Krajinovic M, Labuda D, Richer C, et al (1999). Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms. Blood, 93, 1496-501.
- Krajinovic M, Lamothe S, Labuda D, et al (2004). Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Blood, 103, 252-7. https://doi.org/10.1182/blood-2003-06-1794
- Li X L, Yu F, Zhang Y, et al (2011). [Study on the association between 5, 10-methylenetrahydrofolate reductase C677T polymorphism and acute lymphoblastic leukemia risk: a Meta-analysis]. Zhonghua Liu Xing Bing Xue Za Zhi, 32, 1030-6.
- Lightfoot TJ, Johnston WT, Painter D, et al (2010). Genetic variation in the folate metabolic pathway and risk of childhood leukemia. Blood, 115, 3923-9. https://doi.org/10.1182/blood-2009-10-249722
- Liu JX, Chen JP, Tan W, Lin D X (2008). [Association between mthfr gene polymorphisms and toxicity of HDMTX chemotherapy in acute lymphocytic leukemia]. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 16, 488-92.
- Lv L, Wu C, Sun H, et al (2010). Combined 677CC/1298AC genotypes of methylenetetrahydrofolate reductase (MTHFR) reduce susceptibility to precursor B lymphoblastic leukemia in a Chinese population. Eur J Haematol, 84, 506-12. https://doi.org/10.1111/j.1600-0609.2010.01430.x
- Mantel N, Haenszel W (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst, 22, 719-48.
- McNeer JL (2011). The complex interplay between folate metabolism and risk of acute lymphoblastic leukemia. Leuk Lymphoma, 52, 1621-2. https://doi.org/10.3109/10428194.2011.591010
- Nelen WL, Bulten J, Steegers EA, et al (2000). Maternal homocysteine and chorionic vascularization in recurrent early pregnancy loss. Hum Reprod, 15, 954-60. https://doi.org/10.1093/humrep/15.4.954
- Oh D, Kim NK, Jang MJ, et al (2007). Association of the 5, 10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) polymorphisms in Korean patients with adult acute lymphoblastic leukemia. Anticancer Res, 27, 3419-24.
- Oliveira E, Alves S, Quental S, et al (2005). The MTHFR C677T and A1298C polymorphisms and susceptibility to childhood acute lymphoblastic leukemia in Portugal. J Pediatr Hematol Oncol, 27, 425-9. https://doi.org/10.1097/01.mph.0000177513.81465.94
- Petra BG, Janez J, Vita D (2007). Gene-gene interactions in the folate metabolic pathway influence the risk for acute lymphoblastic leukemia in children. Leuk Lymphoma, 48, 786-92. https://doi.org/10.1080/10428190601187711
- Reddy H, Jamil K (2006). Polymorphisms in the MTHFR gene and their possible association with susceptibility to childhood acute lymphocytic leukemia in an Indian population. Leuk Lymphoma, 47, 1333-9. https://doi.org/10.1080/10428190600562773
- Robien K, Ulrich C M (2003). 5, 10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. Am J Epidemiol, 157, 571-82. https://doi.org/10.1093/aje/kwg024
- Scelo G, Metayer C, Zhang L, et al (2009). Household exposure to paint and petroleum solvents, chromosomal translocations, and the risk of childhood leukemia. Environ Health Perspect, 117, 133-9. https://doi.org/10.1289/ehp.11927
- Schnakenberg E, Mehles A, Cario G, et al (2005). Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population. BMC Med Genet, 6, 23.
- Skibola CF, Smith MT, Kane E, et al (1999). Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci U S A, 96, 12810-5. https://doi.org/10.1073/pnas.96.22.12810
- Sood S, Das R, Trehan A, et al (2010). Methylenetetrahydrofolate reductase gene polymorphisms: association with risk for pediatric acute lymphoblastic leukemia in north Indians. Leuk Lymphoma, 51, 928-32. https://doi.org/10.3109/10428191003719023
- Thirumaran RK, Gast A, Flohr T, et al (2005). MTHFR genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemia. Blood, 106, 2590-1; author reply 1-2. https://doi.org/10.1182/blood-2005-04-1719
- Tong N, Fang Y, Li J, et al (2010). Methylenetetrahydrofolate reductase polymorphisms, serum methylenetetrahydrofolate reductase levels, and risk of childhood acute lymphoblastic leukemia in a Chinese population. Cancer Sci, 101, 782-6. https://doi.org/10.1111/j.1349-7006.2009.01429.x
- Trabetti E (2008). Homocysteine, MTHFR gene polymorphisms, and cardio-cerebrovascular risk. J Appl Genet, 49, 267-82. https://doi.org/10.1007/BF03195624
- Wang H, Meng L, Zhao L, et al (2012). Methylenetetrahydrofolate reductase polymorphism C677T is a protective factor for pediatric acute lymphoblastic leukemia in the Chinese population: a meta-analysis. Genet Test Mol Biomarkers, 16, 1401-7. https://doi.org/10.1089/gtmb.2012.0184
- Wang J, Zhan P, Chen B, et al (2010). MTHFR C677T polymorphisms and childhood acute lymphoblastic leukemia: a meta-analysis. Leuk Res, 34, 1596-600. https://doi.org/10.1016/j.leukres.2010.03.034
- Wiemels JL, Smith RN, Taylor GM, et al (2001). Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc Natl Acad Sci U S A, 98, 4004-9. https://doi.org/10.1073/pnas.061408298
- Yan J, Yin M, Dreyer ZE, et al (2012). A meta-analysis of MTHFR C677T and A1298C polymorphisms and risk of acute lymphoblastic leukemia in children. Pediatr Blood Cancer, 58, 513-8. https://doi.org/10.1002/pbc.23137
- Yang L, Liu L, Wang J, et al (2011). Polymorphisms in folate-related genes: impact on risk of adult acute lymphoblastic leukemia rather than pediatric in Han Chinese. Leuk Lymphoma, 52, 1770-6. https://doi.org/10.3109/10428194.2011.578186
- Yeoh AE, Lu Y, Chan JY, et al (2010). Genetic susceptibility to childhood acute lymphoblastic leukemia shows protection in Malay boys: results from the Malaysia-Singapore ALL Study Group. Leuk Res, 34, 276-83. https://doi.org/10.1016/j.leukres.2009.07.003
- Yu H, Jin RM, Bai Y, et al (2006). The relationship between the methylenetetrahydrofolate reducase C677T gene polymorphism and acute lymphocytic leukemia in childrn. J Clin Hematol, 19, 205-6, 9.
- Zanrosso CW, Hatagima A, Emerenciano M, et al (2006). The role of methylenetetrahydrofolate reductase in acute lymphoblastic leukemia in a Brazilian mixed population. Leuk Res, 30, 477-81. https://doi.org/10.1016/j.leukres.2005.08.008
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