Abstract
Background5,10-methylenetetrahydrofolate reductase (MTHFR) variants, C677T and A1298C, have been reported to be associated with decreased risk of acute lymphoblastic leukemia (ALL). However, results derived from individually underpowered studies are conflicting. We carried out an updated meta-analysis on the association between MTHFR polymorphisms and ALL risk.MethodsRelevant publications were searched through PUBMED and EMBASE databases. The associations between MTHFR C677T and A1298C polymorphisms and the risk of ALL were evaluated by odds ratios (ORs). The heterogeneity and publication bias were estimated. Meta-regression analysis was performed to evaluate the potential sources of heterogeneity.ResultsC677T polymorphism was associated with a reduced risk of ALL (allele contrast: ORRE = 0.91, 95% CI: 0.83-0.99). Subgroup analysis showed MTHFR C677T variant was associated with decreased susceptibility to ALL in children and Caucasians. Meta-regression showed the logOR for the association between T allele and ALL increased as sex ratio (M/F) in the case group increased (P = 0.01). Regarding A1298C polymorphism, no significant association was observed (allele contrast: ORRE = 1.01, 95% CI: 0.91-1.11). There was no publication bias for C677T or A1298C polymorphism.ConclusionsThe present meta-analysis suggests that the C677T polymorphism, not A1298C, in MTHFR gene is associated with a decreased risk of ALL, particularly among children and Caucasians subjects. Our findings suggest that the influence of the C677T polymorphism on ALL susceptibility is modified by sex ratio in cases (M/F). Since folate intake may be a possible confounding factor, including this factor in future prospective studies is warranted. Further meta-analysis studies should be at least stratified for folate levels and gender to give more powerful and informative results.
Highlights
Acute lymphoblastic leukemia (ALL) is a malignant neoplasm of the lymphocyte precursor cells or lymphoblasts. This hematologic malignancy accounts for 75% of pediatric leukemias and 20% of adult leukemias, with an early peak incidence at 2 to 5 years of age followed by a second peak after age 50 years[1,2,3]
Selection criteria and identification of studies We conducted a comprehensive search of PUBMED and EMBASE databases for publications on the association between MTHFR C677T and/or A1298C variant(s) and ALL, using the following search terms: methylenetetrahydrofolate reductase or MTHFR; leuk(a)emia, acute lymphocytic or acute lymphoblastic; and gene, polymorphism or genetic variant
No association between A1298C polymorphism and risk of ALL observed Regarding the MTHFR A1298C polymorphism, no significant association was observed in any genetic model test when all the 29 studies pooled together
Summary
Acute lymphoblastic leukemia (ALL) is a malignant neoplasm of the lymphocyte precursor cells or lymphoblasts. This hematologic malignancy accounts for 75% of pediatric leukemias and 20% of adult leukemias, with an early peak incidence at 2 to 5 years of age followed by a second peak after age 50 years[1,2,3]. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is a key player in folate metabolism, which irreversibly catalyzes the reduction of 5,10-methylenetetrahydrofolate (5,10-methylene THF) into 5-methyltetrahydrofolate (5-methyl THF), the predominant circulatory form of folate (Additional file 1: Figure S1) [5]. Two common polymorphisms in the MTHFR gene, C677T (rs1801133) and A1298C (rs1801131) contribute to reduced enzyme activity and disturbance in folate metabolism. Severe enzymatic activity deficiency results in hyperhomocysteinaemia and is linked to increased risk of neural tube defects and vascular diseases[8,9,10,11]
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