Abstract
To clarify the effect of the A1298C variant of methylenetetrahydrofolate reductase (MTHFR) gene on the risk of acute lymphoblastic leukemia (ALL), an updated meta-analysis was performed. Electronic literature search was carried out in PubMed to collect relevant articles. Pooled odds ratios (OR) and stratification analysis were achieved under different genetic comparison models, age and ethnicity. A total of 46 articles including 7020 cases and 12,114 controls were enrolled. Overall, no significant association was observed for the MTHFR A1298C variant on the risk of ALL in any genetic model test, when all the studies pooled together (OR ~ 1 0.91; p > 0.05). In subgroup analyses stratified by age and ethnicity, the MTHFR A1298C reduce the risk of ALL in adult under allele contrast (OR = 0.88; [0.72; 1.09], p = 0.23) mainly in Caucasian populations. The present meta-analysis provides evidence that the A1298C variant of MTHFR gene is unlikely to be a major risk gene for childhood ALL.
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References
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 98:4004–4009
Miranda-Vilela AL (2013) Role of Methylenetetrahydrofolate reductase (Mthfr), glutathione S-transferases (Gsts M1 and T1) and haptoglobin (Hp) gene polymorphisms in susceptibility to chronic myeloid leukemia (Cml). J Hematol Thromboemb Dis 1:2
Kim YI (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10:66–88
Duthie SJ, Narayanan S, Brand GM, Pirie L, Grant G (2002) Impact of folate deficiency on DNA stability. J Nutr 132:2444S-S2449
Yamada K, Chen Z, Rozen R, Matthews RG (2001) Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc Natl Acad Sci U S A 98:14853–14858
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 96:12810–12815
Barbosa CG, Souza CL et al (2008) Methylenetetrahydrofolate reductase polymorphisms in myeloid leukemia patients from Northeastern Brazil. Genet Mol Biol 31:29–32
Frikha R (2020) Assessment of the relationship between methylenetetrahydrofolate reductase polymorphism and acute lymphoblastic leukemia: evidence from an updated meta-analysis. J Oncol Pharm Pract 26(7):1598–1610
Roy Moulik N, Parveen F, Kumar A, Awasthi S, Agrawal S (2014) MTHFR gene polymorphism in acute lymphoblastic leukemia among North Indian children: a case–control study and meta-analysis updated from 2011. J Hum Genet 59:397–404
Xiao Y, Deng TR, Su CL, Shang Z (2014) Methylenetetrahydrofolate reductase polymorphisms and susceptibility to acute lymphoblastic leukemia in a Chinese population: a meta-analysis. Oncol Res Treat 37:576–582
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 58:513–518
Egger M, Davey SG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–34
Martorell-Marugan J, Toro-Dominguez D, Alarcon-Riquelme ME, Carmona-Saez P (2017) MetaGenyo: a web tool for meta-analysis of genetic association studies. BMC Bioinform 18:563
Kałużna EM, Strauss E, Świątek-Kościelna B et al (2017) The methylenetetrahydrofolate reductase 677T–1298C haplotype is a risk factor for acute lymphoblastic leukemia in children. Medicine 96:e9290
Zou R, He X, Wu Y et al (2017) TS gene polymorphisms correlate with susceptibility to acute lymphocytic leukemia in children. Med Sci Monit 23:3095–3104
Liu P, Zhang M, Xie X, Jin J, Holman CDAJ (2015) Polymorphisms of 5,10-methylenetetrahydrofolate reductase and thymidylate synthase, dietary folate intake, and the risk of leukemia in adults. Tumor Biol 37:3265–3275
Gutiérrez-Álvarez O, Lares-Asseff I, Galaviz-Hernández C et al (2016) Involvement of MTHFR and TPMT genes in susceptibility to childhood acute lymphoblastic leukemia (ALL) in Mexicans. Drug Metab Person Ther 31(1):41–46
Mosaad YM, Abousamra NK, Elashery R et al (2015) Methylenetetrahydrofolate reductaseC677TandA1298Cpolymorphism and susceptibility to acute lymphoblastic leukemia in a cohort of Egyptian children. Leuk Lymphoma 56:2699–2705
Fletcher O, Pei J-S, Hsu C-M et al (2015) The association of methylenetetrahydrofolate reductase genotypes with the risk of childhood leukemia in Taiwan. PLoS ONE 10:e0119776
Sazawal S, Chaubey R, Kaur P et al (2013) MTHFR gene polymorphisms and the risk of acute lymphoblastic leukemia in adults and children: a case control study in India. Indian J Hematol Blood Transf 30:219–225
Kreile M, Rots D, Piekuse L et al (2014) Lack of association between polymorphisms in genes MTHFR and MDR1 with risk of childhood acute lymphoblastic leukemia. Asian Pac J Cancer Prev 15:9707–9711
Li X, Liao Q, Zhang S, Chen M (2014) Association of methylenetetrahytrofolate reductase (MTHFR) C677T and A1298C polymorphisms with the susceptibility of childhood acute lymphoblastic leukaemia (ALL) in Chinese population. Eur J Med Res 19:5
Bellampalli R, Phani NM, Bhat KG et al (2015) Significance of 5,10-methylenetetrahydrofolate reductase gene variants in acute lymphoblastic leukemia in Indian population: an experimental, computational and meta-analysis. Leuk Lymphoma 56:1450–1459
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
Nikbakht M, MalekZadeh K, Kumar Jha A et al (2012) Polymorphisms of MTHFR and MTR genes are not related to susceptibility to childhood ALL in North India. Exp Oncol 34:43–48
Karathanasis NV, Stiakaki E, Goulielmos GN, 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
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 52:1770–1776
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 101:782–786
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 51:928–932
Lightfoot TJ, Roman E, Smith MT, Skibola CF (2010) Acute lymphoblastic leukaemia in children—is there a role for MTHFR? Br J Haematol 149:797–8 (author reply 9–800)
Chan JY, Ugrasena DG, Lum DW, Lu Y, Yeoh AE (2011) Xenobiotic and folate pathway gene polymorphisms and risk of childhood acute lymphoblastic leukaemia in Javanese children. Hematol Oncol 29:116–123
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 34:276–283
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 84:506–512
Sadananda Adiga MN, Chandy S, Ramachandra N et al (2010) Methylenetetrahydrofolate reductase gene polymorphisms and risk of acute lymphoblastic leukemia in children. Indian J Cancer 47:40–45
de Jonge R, Tissing WJ, Hooijberg JH et al (2009) Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood 113:2284–2289
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 51:178–182
Kamel AM, Moussa HS, Ebid GT, Bu RR, Bhatia KG (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
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 48:786–792
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 27:3419–3424
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 30:477–481
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 26:2879–2881
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 47:1333–1339
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)
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
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 27:425–429
Krajinovic M, Lamothe S, Labuda D et al (2004) Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Blood 103:252–257
Gemmati D, Ongaro A, Scapoli GL 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 13:787–794
Chiusolo P, Reddiconto G, Cimino G et al (2004) Methylenetetrahydrofolate reductase genotypes do not play a role in acute lymphoblastic leukemia pathogenesis in the Italian population. Haematologica 89:139–144
Franco RF, Simoes BP, Tone LG, Gabellini SM, Zago MA, Falcao RP (2001) The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukaemia. Br J Haematol 115:616–618
Zintzaras E, Doxani C, Rodopoulou P et al (2012) Variants of the MTHFR gene and susceptibility to acute lymphoblastic leukemia in children: a synthesis of genetic association studies. Cancer Epidemiol 36:169–176
Onciu M (2009) Acute lymphoblastic leukemia. Hematol Oncol Clin North Am 23:655–674
Koppen IJ, Hermans FJ, Kaspers GJ (2010) Folate related gene polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia. Br J Haematol 148:3–14
Lien SA, Young L, Gau BS, Shiao SPK (2017) Meta-prediction of MTHFR gene polymorphism-mutations, air pollution, and risks of leukemia among world populations. Oncotarget 8:4387–98
Pereira TV, Rudnicki M, Pereira AC, Pombo-de-Oliveira MS, Franco RF (2006) 5,10-Methylenetetrahydrofolate reductase polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15:1956–1963
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Frikha, R. Lack of Impact of the A1298C MTHFR on the Risk of Childhood Acute Lymphoblastic Leukemia: Evidence from a Meta-analysis. Indian J Hematol Blood Transfus 38, 255–263 (2022). https://doi.org/10.1007/s12288-021-01453-6
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DOI: https://doi.org/10.1007/s12288-021-01453-6