European Journal of Epidemiology

, Volume 21, Issue 7, pp 501–510 | Cite as

A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia

  • Elias ZintzarasEmail author
  • Theocharis Koufakis
  • Panayiotis D. Ziakas
  • Paraskevi Rodopoulou
  • Stavroula Giannouli
  • Michael Voulgarelis


A meta-analysis of case–control studies that investigated the association between the C677T and/or A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and acute lymphoblastic leukemia (ALL) was carried out. Pooled odds ratios (OR) of various genetic contrasts of each polymorphism were estimated using random (RE) and fixed effects (FE) models. Pooled ORs for combined genotypes and haplotypes were estimated after adjustment for study effect using a log-linear model and the expectation–maximization algorithm in combination with log-linear modeling, respectively. The recessive model for allele 1298C produced a rather marginal association: RE OR: 0.67; 95% confidence interval (CI): 0.46–0.99 and FE OR: 0.64; 95% CI: 0.49–0.84. In Caucasians, the results of the recessive model for allele 1298C was consisted with a protective effect of ALL development: FE OR: 0.63; 95% CI: 0.46–0.87. In childhood ALL, according to the results of the allele contrast and the recessive model for 677T allele it was conceivable that a protective effect exist: RE OR = 0.74; 95% CI: 0.57–0.96 and RE OR: 0.69; 95% CI: 0.51–0.94, respectively. The combined genotypes produced significant pooled OR for the 677CC/1298CC relative to 677CC/1298AA (OR: 0.54; 95% CI: 0.36–0.80). The haplotype 677C/1298C might be more protective to ALL relative to haplotype 677C/1298A (OR: 0.77; 95% CI: 0.61–0.97). When studies not in Hardy–Weinberg equilibrium (HWE) were corrected to account for departures from HWE, then, the pattern of results remained the same. Overall, there is high heterogeneity between the studies in both polymorphisms. A differential magnitude of effect in large versus small studies and alteration of early extremes effects existed.


Genotypes Haplotypes Hardy–Weinberg equilibrium Leukemia Log-linear model Meta-analysis MTHFR 


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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Elias Zintzaras
    • 1
    • 3
    Email author
  • Theocharis Koufakis
    • 1
  • Panayiotis D. Ziakas
    • 1
    • 2
  • Paraskevi Rodopoulou
    • 1
  • Stavroula Giannouli
    • 2
  • Michael Voulgarelis
    • 2
  1. 1.Evidence-Based Medicine Unit, Department of BiomathematicsUniversity of Thessaly School of MedicineLarissaGreece
  2. 2.Department of Medicine PathophysiologyUniversity of Athens School of MedicineAthensGreece
  3. 3.Department of BiomathematicsUniversity of Thessaly School of MedicineLarissa Greece

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