12 March 2015: Meta-Analysis
Association between MTHFR C677T Polymorphism and Risk of Acute Lymphoblastic Leukemia: A Meta-Analysis Based on 51 Case-Control Studies
Su-yi Li CDE , Jie-yu Ye CDG , En-yu Liang BF , Li-xia Zhou BF , Mo Yang AEG
DOI: 10.12659/MSM.892835
Med Sci Monit 2015; 21:740-748
Abstract
BACKGROUND: Studies and systematic reviews have reached inconsistent conclusions on the role of 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphism C677T in acute lymphoblastic leukemia (ALL) risk.
MATERIAL AND METHODS: The present meta-analysis comprising of 51 case-control studies, including 7892 cases and 14 280 controls was performed to reevaluate the association between MTHFR C677T polymorphism and ALL risk.
RESULTS: Statistical differences were found in the dominant model (TT+CT vs. CC, odd ratio (OR)=0.89, 95% CI, 0.79–1.00, P=0.04) and the CT vs. CC (OR=0.89, 95% CI, 0.80–1.00, P=0.05), but not in the allele contrast model (T vs. C, OR=0.92, 95% CI, 0.84–1.01, P=0.08), additive model (TT vs. CC, OR=0.87, 95% CI, 0.73–1.05, P=0.15), or recessive model (TT vs. CT+CC, OR=0.94, 95% CI, 0.81–1.10, P=0.44) in overall populations. In the subgroup analyses stratified by age (children and adults) and ethnicity (Asian and Caucasian), no significant associations between MTHFR C677T polymorphism and ALL risk were observed.
CONCLUSIONS: The current study found no sufficient evidence of a protective role of MTHFR C677T polymorphism in ALL susceptibility.
Keywords: Case-Control Studies, Ethnic Groups - genetics, Genetic Association Studies, Genetic Predisposition to Disease, Methylenetetrahydrofolate Reductase (NADPH2) - genetics, Polymorphism, Single Nucleotide - genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics, Publication Bias, Risk Factors
Background
Acute lymphoblastic leukemia (ALL) originates from an expansion of monoclonal malignant T or B lymphoid cells and can occur at any age, with peak incidence at 2–5 years of age [1]. The etiology of ALL is complex; it is considered to be associated with both endogenous and exogenous factors. Confirmed risk factors include congenital genetic disorders (e.g., Down syndrome, neurofibromatosis, Fanconi’s anemia) and adverse environmental exposures (e.g., ionizing radiation, benzene). However, these risk factors only account for less than 10% of ALL patients [2], leaving most of the patients with still unknown causes.
With the advent of the genome-wide association study (GWAS) era, many researchers began to focus on genetic variability in drug metabolism, DNA repair, and cell-cycle checkpoints that may interact with environmental, dietary, maternal, and other external factors to affect leukemogenesis. Currently, it has been determined that variations of the genes RID5B, IKZF1, CEBPA, and CDKN2A/B are associated with increased susceptibility to ALL. However, the number of confirmed genetic risk factors is still limited, with many remaining to be identified [3–5].
Methylenetetrahydrofolate reductase (MTHFR) is the most critical enzyme in the folate metabolism [6,7], catalyzing irreversible conversion of 5,10-methylenetetrahydrofolate (5,10-MTHF) to 5-methyltetrahydrofolate (5-MTHF), which is the predominant circulating form of folate. 5,10-MTHF is the intracellular coenzyme form of folate and is required for conversion of uridylate to thymidylate, which inhibits misincorporation of uridylate into DNA. Thus, folate is an important factor in DNA synthesis. In addition, MTHFR causes methylation of homocysteine into methionine, leading to methylation of DNA. Many studies have reported that aberrant DNA methylation plays important roles in the pathogenesis of many hematological malignancies through regulation of gene transcription and imprinting [8–13].
MTHFR gene is localized on chromosome 1p36.3 [14] and is highly polymorphic. The variant genotypes result in decreased MTHFR enzyme activity. Decreased MTHFR activity may result in mistakes during DNA replication, leading to disturbance in 5,10-MTHF metabolism, which is essential for DNA methylation, repair, and synthesis.
Previous studies investigated the association between MTHFR C677T polymorphism and ALL risk. However, findings from these studies were conflicting. Some studies [7,18–21] concluded that MTHFR C677T polymorphism was associated with a reduced ALL risk, some [22–26] indicated insignificant associations between the gene and ALL risk, and others [27] reported an increased ALL risk with MTHFR C677T. Likewise, many meta-analyses [28–36] addressing this association also arrived at inconsistent conclusions.
For independent case-control studies, this inconsistency may be attributed partly to a limited sample size in some, with insufficient statistical power to demonstrate a significant association; they also involved different populations [29] and adopted different sampling strategies. For meta-analyses, different searching strategies and inclusion criteria might have resulted in different studies included, leading to different conclusions.
There have been many recent case-control studies [22,23,27,37–39] since the previously published meta-analyses [28–33]. This new evidence necessitates reassessment of the association between MTHFR C677T polymorphism and ALL risk, as performed in this updated meta-analysis. We hope that this meta-analysis of the most comprehensive literature addressing the association will yield more convincing evidence to determine the role of MTHFR C677T polymorphism in ALL risk.
Material and Methods
LITERATURE SEARCH:
A systematic search was conducted by 2 independent authors to identify studies on the association between MTHFR C677T polymorphism and ALL risk. Search term “((methylenetetrahydrofolate reductase) OR (MTHFR gene)) AND (polymorphism OR genetics) AND (acute lymphoblastic leukemia)” was used in 3 electronic databases (PubMed, Cochrane Library, and Wanfang Data) from inception to 31st Dec, 2013. The references of recently published meta-analyses [28–33] were also checked. There was no restriction of publication language.
INCLUSION AND EXCLUSION CRITERIA:
The studies included for the present meta-analysis fulfilled the following criteria: (a) case-control design, (b) investigating the association between MTHFR C677T polymorphism and ALL risk, either in adult or in childhood, and (c) published reports providing sufficient data to calculate the odds ratio (OR) and its 95% confidence interval (CI). The exclusion criteria were: (a) not a case-control design, (b) not providing effective data, or (c) duplicated reports from the same group of patients.
STUDY IDENTIFICATION:
Two authors independently screened titles of all studies retrieved. The abstract of any study that was potentially relevant to the topic was reviewed. The full text was obtained if inadequate information was acquired from the abstract. The corresponding author was consulted for the final decision if any disagreement on eligibility existed between the first 2 reviewers.
DATA EXTRACTION:
Two authors participated in data extraction independently. Disagreement was resolved by discussion and the corresponding author’s opinion was asked for when necessary. Data were collected from all studies available for meta-analysis and information on general characteristics of the eligible studies and patients.
OUTCOMES FOR META-ANALYSIS:
The association between MTHFR C677T polymorphism and ALL risk was evaluated using the following 5 models: allele contrast (T vs. C), additive model (TT vs. CC), recessive model (TT vs. CC+CT), dominant model (TT+CT vs. CC), and heterozygote vs. wild-type homozygous (CT vs. CC) [32,40].
The outcomes included results of the above 5 models for overall populations and those for subgroup analyses stratified by age (children and adults, the age cut-off values for children and adult complied with the studies included) and ethnicity (Asian and Caucasian).
STATISTICAL ANALYSIS:
Statistical heterogeneity was evaluated using I2 statistics [41], which can be calculated from basic results obtained from a typical meta-analysis as I2=100% × (Q–df)/Q, where Q is Cochrane’s heterogeneity statistic and df is the degrees of freedom [42]. An I2 value of 0% represents no heterogeneity, with values of 25%, 50%, 75%, or more represent low, moderate, high, and extreme heterogeneity, respectively. For outcomes of heterogeneity, when P>0.05, a fixed-effects model was used for analyses. Otherwise, a random-effects model was adopted for P≤0.05. In this study, pooled odd ratios (OR) and their 95% confidence intervals (CI) from all eligible studies were used to assess the strength for the association between MTHFR C677T polymorphism and ALL risk according to the 5 models. The potential for publication bias was estimated by Begg’s test (funnel plot method) and Egger’s linear regression test (P≤0.05 indicated a statistically significant publication bias) [43].
The meta-analysis was performed using Review Manager 5.2 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012) for outcome measures. A
Results
STUDY SELECTION AND CHARACTERISTICS:
The search process and search outcomes are listed in Figure 1. A total of 179 potentially relevant studies were identified. After the titles, abstracts, and full texts were screened and reviewed, 51 published studies [7,18–27,37–39,44–80] with a total of 7892 cases and 14 280 controls met all the inclusion criteria. Of all the eligible studies, 41 were published in English and 10 were in Chinese. Information about general characteristics of the eligible studies and patients are listed in Table 1.
OUTCOMES FOR OVERALL POPULATIONS: As shown in Table 2, no significant associations were identified in the allele contrast model [OR 0.92, 95% CI (0.84, 1.01), P=0.08], additive model [OR 0.87, 95% CI (0.73, 1.05), P=0.15], or recessive model [OR 0.87, 95% CI (0.73, 1.05), P=0.15]. However, statistically significant associations were found in the dominant model [OR 0.89, 95% CI (0.79, 1.00), P=0.04] (Table 2) and the CT vs. CC model [OR 0.89, 95% CI (0.80, 1.00), P=0.05] (Table 2).
OUTCOMES FOR SUBGROUP ANALYSES STRATIFIED BY AGE: A total of 35 studies investigated the association in children. Results revealed insignificant associations between MTHFR C677T polymorphism and ALL risk in all 5 models [Allele contrast model (P=0.09), additive model (P=0.13), recessive model (P=0.34), dominant model (P=0.07), CT vs. CC model (P=0.11)] (Table 2).
Nine studies reported the association in adults. Similarly, none of the 5 models revealed significant associations between MTHFR C677T polymorphism and ALL risk [Allele contrast model (P=0.57), additive model (P=0.47), recessive model (P=0.63), dominant model (P=0.57), CT vs. CC model (P=0.40)] (Table 2).
OUTCOMES FOR SUBGROUP ANALYSES STRATIFIED BY ETHNICITY: Results of 26 studies showed no significant associations between MTHFR C677T polymorphism and ALL risk in Asian populations [Allele contrast model (P=0.39), additive model (P=0.53), recessive model (P=0.93), dominant model (P=0.22), and CT vs. CC model (P=0.15)] (Table 3). Likewise, no significant associations were identified between MTHFR C677T polymorphism and ALL risk in Caucasian populations [Allele contrast model (P=0.24), additive model (P=0.36), recessive model (P=0.56), dominant model (P=0.22), CT vs. CC model (P=0.29)] (Table 3).
PUBLICATION BIAS:
Begg’s test and Egger’s linear regression test were performed to evaluate the publication bias of all eligible studies. Evaluation of publication bias for
Discussion
Although numerous case-control studies and meta-analyses have investigated the association between MTHFR C677T polymorphism and risk for developing ALL, no definite conclusions have been reached on the role of
Although many previous meta-analyses (28–36) focused on the association between MTHFR C677T polymorphism and ALL risk, conflicting conclusions derived from these studies made the role of the gene unclear. Many factors might have accounted for the disagreements. One possible reason was related to the different search strategies and databases used for the search. A reliable and convincing meta-analysis must be based on a comprehensive search of all eligible studies. To minimize selection bias, 2 measures were taken in the present study. First, we searched the Wanfang database to include all eligible studies in Chinese patients. Second, we reviewed the references in previously published meta-analyses. Consequently, the current study was based on the largest possible amount of published data, providing the most comprehensive information on the association under investigation.
In overall population analysis based on varied populations from 22 countries, insignificant differences were identified in the allele contrast model (
Similarly, subgroup analyses on ethnicity revealed insignificant associations between MTHFR C677T polymorphism and ALL risk in Asians and Caucasians. Consistent and inconsistent findings were identified regarding the ethnic difference between the present study and previously published meta-analyses. With regard to the investigations in Asian populations, Tong et al. [32] indicated that MTHFR C677T polymorphism was not associated with ALL susceptibility, which was supported by reports by Zintzaras et al. [28] and Jiang et al. [81]. However, Yan et al. [29] and Wang et al. [31] concluded that MTHFR C677T polymorphism was a protective factor in Asians. Quite different from most of the previous meta-analyses of reduced risk with MTHFR C677T polymorphism in Caucasians, we found no protective role of this gene polymorphism in Caucasians. Therefore, due to continuing controversies, more surveys are needed to reach a precise conclusion, both in Asians and Caucasians. Although the present study found no evidence for a protective effect of MTHFR C677T polymorphism in Asians or Caucasians, differences did exist among different ethnicities as Yan et al. [29] stated, like varied allele frequencies, possible gene-gene interactions from different genetic backgrounds and possible gene-environment interactions from different lifestyles.
The larger number of eligible studies in the present study may lend it sufficient power to provide convincing evidence on the association between MTHFR C677T polymorphism and ALL risk. However, the larger sample size does not mean the study is without limitations. One limitation of the present meta-analysis is the still high heterogeneity among the studies included, which was probably due to various biases during the processes of patient selection, sample testing, and outcome reporting. Another limitation was lack of evaluation of gene-gene interactions. It has been indicated that the etiology of ALL is complex [1], involving gene-gene interactions as well as gene-environment interactions. Apart from the influence of the
Conclusions
The present study found no evidence that MTHFR C677T polymorphism plays a protective role in the development of ALL in children, adults, Asians, or Caucasians.
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