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ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 7  |  Page : 210-214

The association between methylenetetrahydrofolate reductase C677 > T polymorphisms and risk of pediatric acute lymphoblastic leukemia in Asia


Department of Hematology, The Children's Hospital of Fuzhou, Fuzhou 350005, China

Date of Web Publication29-Nov-2014

Correspondence Address:
Shiguang Lin
Department of Hematology, The Children's Hospital of Fuzhou, Fuzhou 350005
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.145877

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 > Abstract 

Objective: The association between methylenetetrahydrofolate reductase (MTHFR) C677 > T polymorphisms and pediatric acute lymphoblastic leukemia (ALL) risk in Asia is controversial. The aim of this meta-analysis was to further assess the relationship between MTHFR C677 > T polymorphisms and pediatric ALL for Chinese children.
Materials and Methods: Studies about the MTHFR C677 > T polymorphisms and pediatric ALL risk were searched in the Medline, PubMed, EMBASE, Wanfang and CNIK databases. The genotype of the case and control group were extracted and pooled by meta-analysis. The association between ALL risk and C677 > T polymorphisms was demonstrated by odds ratio (OR) and its 95% confidence interval (CI).
Results: Twelve articles were included in this study with 1803 ALL cases and 4146 controls. In recessive genetic model (TT vs. CC + CT), the OR was 0.37 (95%CI: 0.31-0.43); in dominant genetic model (TT + CT vs. CC) the OR was 0.94 (95%CI: 0.82-1.06); and in the homozygous model the OR was 0.84 (95%CI: 0.69-1.03).
Conclusion: The results indicated that Asian children with TT genotype of MTHFR gene may have less risk of developing ALL.

Keywords: Acute lymphoblastic leukemia, children, methylenetetrahydrofolate reductase gene, polymorphisms


How to cite this article:
Lin S, Liu Q, Zeng X. The association between methylenetetrahydrofolate reductase C677 > T polymorphisms and risk of pediatric acute lymphoblastic leukemia in Asia. J Can Res Ther 2014;10, Suppl S3:210-4

How to cite this URL:
Lin S, Liu Q, Zeng X. The association between methylenetetrahydrofolate reductase C677 > T polymorphisms and risk of pediatric acute lymphoblastic leukemia in Asia. J Can Res Ther [serial online] 2014 [cited 2019 Aug 20];10:210-4. Available from: http://www.cancerjournal.net/text.asp?2014/10/7/210/145877


 > Introduction Top


Epidemiological studies revealed that folic acid metabolism abnormal or inadequate intake may increase the risk of developing acute lymphoblastic leukemia (ALL). [1] Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the MTHFR gene. [2] MTHFR is on chromosome 1 location p36.3 in humans [2] composed of an N-terminal catalytic domain and a C-terminal regulatory domain. The MTHFR nucleotide at position 677 has two possibilities: C (cytosine) or T (thymine). C at position 677 (leading to an alanine at amino acid 222) is the normal allele. The 677T allele (leading to a valine substitution at amino acid 222) encodes a thermolabile enzyme with reduced activity. The association of MTHFR C677 > T polymorphisms and pediatric ALL risk was previously reported. But the results were not conclusive.


 > MaterialS and methods Top


0 Identification and eligibility of relevant studies

The articles related to MTHFR C677 > T polymorphisms and pediatric ALL risk was searched in the databases of Medline, PubMed, EMBASE, Wanfang and CNIK before July 2014. The search terms were "MTHFR" or "MTHFR," "leukemia," "childhood" or "children" "pediatric" and "polymorphisms." The references of the included studies were also reviewed in order to further include the potential articles. All the case-control and cohort study related to the MTHFR C677 > T polymorphisms and pediatric ALL risk were reviewed and included if: (1) The age of included subjects was ≤ 18; (2) the ALL was confirmed by gold diagnosis standard; (3) the distribution of genotype can be extracted from each included paper; (4) the patients included were restrict to Asian children; (5) the publish language were limited to English and Chinese.

Data extraction

The following information of each included study was extracted by two reviewers independently. (1) Author name; (2) year of publication; (3) publish language; (3) country;(4) genotyping methods; (5) Hardy-Weinberg equilibrium; (6) genotype of CC, CT and TT distribution.

Statistical analysis

All the statistical analysis was performed using Stata 11.0 (http://www.stata.com/) and MetaAnalyst 3.1 (http://tuftscaes.org/meta_analyst/). The association between MTHFR C677 > T polymorphisms and pediatric ALL risk was demonstrated by odds ratio (OR) and its 95% confidence interval (CI). The statistical heterogeneity for OR across the included studies was evaluated by Chi-square and I2 . If P < 0.05 for heterogeneity test, the randomized effect method was used to pool the OR. Otherwise, the fixed effect method was used. Two-tailed P < 0.05 was deemed statistical significance.


 > Results Top


0 Articles included in this study

Eighty-eight potential relevant articles were initially identified by searching the data bases. After reviewing the title and abstract 71 papers were excluded because of not suitable for inclusion with 17 articles left. And after reviewing the full text, 5 articles were excluded from the study. Finally, 12 studies including 1803 ALL cases and 4146 controls were included in this meta-analysis. For the included 12 studies, 6 studies were from China, 2 researches from Korea, 2 articles from India, 1 paper from Philippines and 1 form mixed country of Asia. The detailed information of the included papers was shown in [Table 1].
Table 1: Studies investing the MTHFR C677>T polymorphisms and pediatric ALL


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Genotype prevalence

The median ratio CC, CT and TT genotype in ALL children were 0.12 (95%CI: 0.06-0.19), 0.43 (95%CI: 0.36-0.50) and 0.45 (95%CI: 0.35-0.55); and the median ratio CC, CT and TT genotype in control children were 0.14 (95%CI: 0.09-0.20), 0.45 (95%CI: 0.376-0.53) and 0.41 (95%CI: 0.29-0.53). The distribution of genotype was demonstrated in [Figure 1].
Figure 1: The genotype distribution of CC, CT and TT between the acute lymphoblastic leukemia and controls

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Quantitative synthesis

The test for heterogeneity indicated that there was statistical heterogeneity in recessive genetic model (TT vs. CC + CT), dominant genetic model (TT + CT vs. CC) and homozygous model. The OR was pooled by random effect model. In recessive genetic model (TT vs. CC + CT), the OR was 0.37 (95%CI: 0.31-0.43) [Figure 2]; in dominant genetic model (TT + CT vs. CC) the OR was 0.94 (95%CI: 0.82-1.06) [Figure 3]; and in the homozygous model the OR was 0.84 (95%CI: 0.69-1.03) [Figure 4].
Figure 2: The forest plot of (methylenetetrahydrofolate reductase) C677>T polymorphisms and pediatric acute lymphoblastic leukemia for recessive model

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Figure 3: The forest plot of (methylenetetrahydrofolate reductase) C677>T polymorphisms and pediatric acute lymphoblastic leukemia for dominant model

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Figure 4: The forest plot of (methylenetetrahydrofolate reductase) C677>T polymorphisms and pediatric acute lymphoblastic leukemia for homozygous model

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Publication bias

The publication was assessed by Begge's funnel plot and Egger's test. The funnel plot was general symmetry [Figure 5] and Egger's test indicated there was no significant publication bias in the recessive (t = 0.31, P = 0.76), dominant (t = −0.02, P = 0.98) and homologous model (t = −0.17, P = 0.87).
Figure 5: The funnel plot evaluation the publication bias

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 > Discussion Top


For children, the ALL is the most common malignant tumors which account for one-fourth of the total childhood carcinoma cases. [15] It was reported that the incidence rate is approximately 9-10 cases per 100,000 for childhood, with a peak incidence between 2 and 5 years old. [16] The mechanism for childhood ALL is not clear, but some evidence indicated that gene polymorphism was associated with ALL.

Methylenetetrahydrofolate reductase is the rate-limiting enzyme in the methyl cycle, and it is encoded by the MTHFR gene. And published articles showed that MTHFR C677 > T polymorphisms was in association with the development of pediatric ALL. However, the results were not consistent with each other. Tong et al. [7] reported that children with TT genotype has less risk of developing ALL compared with CC or CT genotype. But Hui et al. [3] believe that the ALL risk was significant low in children with CT genotype compared with CC genotype. And there was no statistical difference between TT and CC genotype. In this meta-analysis, we included 12 studies reporting the MTHFR C677 > T polymorphisms and pediatric ALL risk in Asia. Six studies were from China, 2 researches from Korea, 2 articles from India, 1 paper from Philippines and 1 form mixed country of Asia. The median ratio of CC, CT and TT genotype in ALL children were 0.12 (95%CI: 0.06-0.19), 0.43 (95%CI: 0.36-0.50) and 0.45 (95%CI: 0.35-0.55); and the median ratio CC, CT and TT genotype in control children were 0.14 (95%CI: 0.09-0.20), 0.45 (95%CI: 0.376-0.53) and 0.41 (95%CI: 0.29-0.53). The ratio of CC and CT in case and control group was almost the same. But in TT genotype, the TT genotype ratio was lower than that of the control group, indicating the TT genotype may be a protective factor for pediatric ALL. Meta-analysis results showed that in recessive genetic model (TT vs. CC + CT), TT genotype was associated with less risk of developing pediatric ALL. But the in dominant and homozygous model, no relationship between genotype an ALL risk was found.

In summary, Asian children with TT genotype of MTHFR gene may have less risk of developing ALL. However, with a small number of case and controls in each study and significant heterogeneity among the articles, the conclusion of this meta-analysis was limited.

 
 > References Top

1.
Milne E, Royle JA, Miller M, Bower C, de Klerk NH, Bailey HD, et al. Maternal folate and other vitamin supplementation during pregnancy and risk of acute lymphoblastic leukemia in the offspring. Int J Cancer 2010;126:2690-9.  Back to cited text no. 1
    
2.
Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, et al. Human methylenetetrahydrofolate reductase: Isolation of cDNA, mapping and mutation identification. Nat Genet 1994;7:195-200.  Back to cited text no. 2
    
3.
Hui YU, Runming J, Yan B, Wen L, Anxiu X, Zhiquan Z, et al. The relationship between the methylenetetrahydrofolate reductase C677T gene polymorphism and acute lymphocytic leukemia in children. J Clin Hematol 2006;19:205-6, 9.  Back to cited text no. 3
    
4.
Hui LU, Wei W, Zhi-zuo DU, Wen-li Z, Yi W, Shao-yan HU, et al. Relationship between genetic polymorphism of methylenetetrahydrofolate reductase and the risk of childhood acute lymphocytic leukemia. J Clin Pediatr 2011;29:414-7.  Back to cited text no. 4
    
5.
Hua J, Longjun G, Huiliang X, Jing C, Ci P, Hui Y, et al. MTHFR polymorphisms and risk of pediatric acute lymphoblastic leukemia. Chin J Hematol 2004;25:439-40.  Back to cited text no. 5
    
6.
Yang L, Liu L, Wang J, Qiu L, Mi Y, Ma X, et al. Polymorphisms in folate-related genes: Impact on risk of adult acute lymphoblastic leukemia rather than pediatric in Han Chinese. Leuk Lymphoma 2011;52:1770-6.  Back to cited text no. 6
    
7.
Tong N, Fang Y, Li J, Wang M, Lu Q, Wang S, et al. Methylenetetrahydrofolate reductase polymorphisms, serum methylenetetrahydrofolate reductase levels, and risk of childhood acute lymphoblastic leukemia in a Chinese population. Cancer Sci 2010;101:782-6.  Back to cited text no. 7
    
8.
Yeoh AE, Lu Y, Chan JY, Chan YH, Ariffin H, Kham SK, et al. Genetic susceptibility to childhood acute lymphoblastic leukemia shows protection in Malay boys: Results from the Malaysia-Singapore ALL Study Group. Leuk Res 2010;34:276-83.  Back to cited text no. 8
    
9.
Cai FY, WU JR. Relationship between genetic polymorphism of methylenetetrahydrfolate reductase and the risk of childhood acute lymphocytic leukemia. J Leuk Andamp Lymphoma 2012;21:736-8.  Back to cited text no. 9
    
10.
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. Pediatr Blood Cancer 2008;51:178-82.  Back to cited text no. 10
    
11.
Kim NK, Chong SY, Jang MJ, Hong SH, Kim HS, Cho EK, et al. Association of the methylenetetrahydrofolate reductase polymorphism in Korean patients with childhood acute lymphoblastic leukemia. Anticancer Res 2006;26:2879-81.  Back to cited text no. 11
    
12.
Kim HN, Kim YK, Lee IK, Yang DH, Lee JJ, Shin MH, et al. Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies. Leuk Res 2009;33:82-7.  Back to cited text no. 12
    
13.
Reddy H, Jamil K. Polymorphisms in the MTHFR gene and their possible association with susceptibility to childhood acute lymphocytic leukemia in an Indian population. Leuk Lymphoma 2006;47:1333-9.  Back to cited text no. 13
    
14.
Sood S, Das R, Trehan A, Ahluwalia J, Sachdeva MU, Varma N, et al. Methylenetetrahydrofolate reductase gene polymorphisms: Association with risk for pediatric acute lymphoblastic leukemia in north Indians. Leuk Lymphoma 2010;51:928-32.  Back to cited text no. 14
    
15.
Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev 2010;36:277-85.  Back to cited text no. 15
    
16.
Barry EV, Silverman LB. Acute lymphoblastic leukemia in adolescents and young adults. Curr Hematol Malig Rep 2008;3:161-6.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1]



 

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