Journal of Cancer Research and Therapeutics

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


Shiguang Lin, Qin Liu, Xiaoming Zeng 
 Department of Hematology, The Children's Hospital of Fuzhou, Fuzhou 350005, China

Correspondence Address:
Shiguang Lin
Department of Hematology, The Children«SQ»s Hospital of Fuzhou, Fuzhou 350005
China

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.



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;10:210-214


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 2020 Oct 29 ];10:210-214
Available from: https://www.cancerjournal.net/text.asp?2014/10/7/210/145877


Full Text

 Introduction



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



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



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}

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}

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}{Figure 3}{Figure 4}

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}

 Discussion



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.

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