Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
European Journal of Epidemiology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Chen CL, Liu Q, Pui CH, et al. 1997; Higher frequency of glutathione S-transferase deletions in black children with acute lymphoblastic leukemia Blood 89:1701–1707

    PubMed  CAS  Google Scholar 

  2. Sinnett D, Krajinovic M, Labuda D, 2000 Genetic susceptibility to childhood acute lymphoblastic leukemia Leuk Lymphoma 38:447–462

    PubMed  CAS  Google Scholar 

  3. Wiemels JL, Smith RN, Taylor GM, Eden OB, Alexander FE, Greaves MF 2001 United Kingdom Childhood Cancer Study investigators. Methylenetetrahydrofolate reductase (MTHFR polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia Proc Natl Acad Sci USA 98:4004–4009

    Article  PubMed  CAS  Google Scholar 

  4. Robien K, Ulrich CM 2003 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: aHuGE minireview Am J Epidemiol 157:571–582

    Article  PubMed  Google Scholar 

  5. Duthie SJ, McMillan P 1997 Uracil misincorporation in human DNA detected using single cell gel electrophoresis Carcinogenesis 18:1709–1714

    Article  PubMed  CAS  Google Scholar 

  6. Blount BC, Mack MM, Wehr CM, et al. 1997 Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage Proc Natl Acad Sci USA 94:3290–3295

    Article  PubMed  CAS  Google Scholar 

  7. Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE 2000 Biological and clinical implications of the MTHFR C677T polymorphism Trends Pharmacol Sci 22:195–201

    Article  Google Scholar 

  8. Frosst P, Blom HJ, Milos R, et al. 1995 A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase Nat Genet 10:111–113

    Article  PubMed  CAS  Google Scholar 

  9. Botto LD, Yang Q 2000 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A HuGE review Am J Epidemiol 151:862–877

    PubMed  CAS  Google Scholar 

  10. Selhub J 1999 Homocysteine metabolism Annu Rev Nutr 19:217–246

    Article  PubMed  CAS  Google Scholar 

  11. Kang SS, Wong PW, Susmano A, Sora J, Norusis M, Ruggie N 1991 Thermolabile methylenetetrahydrofolate reductase: An inherited risk factor for coronary artery disease Am J Hum Genet 48:536–545

    PubMed  CAS  Google Scholar 

  12. van der Put NM, Steegers-Theunissen RP, Frosst P, et al. 1995; Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida Lancet 346:1070–1071

    Article  PubMed  Google Scholar 

  13. van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, et al. 2004; Homocysteine levels and the risk of osteoporotic fracture N Engl J Med. 350(20):2033–2041

    Article  PubMed  Google Scholar 

  14. McLean RR, Jacques PF, Selhub J, et al. 2004 Homocysteine as a predictive factor for hip fracture in older persons N Engl J Med. 350(20):2042–2049

    Article  PubMed  CAS  Google Scholar 

  15. Freeman JM, Finkelstein JD, Mudd SH 1975; Folate-responsive homocystinuria and “schizophrenia”. A defect in methylation due to deficient 5,10-methylenetetrahydrofolate reductase activity N Engl J Med 292:491–496

    Article  PubMed  CAS  Google Scholar 

  16. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R 1998; A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity Mol Genet Metab 64:169–172

    Article  PubMed  CAS  Google Scholar 

  17. Lievers KJ, Kluijtmans LA, Heil SG, et al. 2001 A 31 bp VNTR in the cystathionine beta-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels Eur J Hum Genet 9:583–589

    Article  PubMed  CAS  Google Scholar 

  18. van der Put NM, Gabreels F, Stevens EM, et al. 1998; A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects? Am J Hum Genet 62:1044–1051

    Article  PubMed  Google Scholar 

  19. Chiusolo P, Reddiconto G, Cimino G, et al. 2004; Methylenetetrahydrofolate reductase genotypes do not play a role in acute lymphoblastic leukaemia pathogenesis in the Italian population Haematologica 89:139–144

    PubMed  CAS  Google Scholar 

  20. Zintzaras E, Ioannidis JP 2004; Heterogeneity testing in meta-analysis of genome searches Genet Epidemiol 24:1–15

    Google Scholar 

  21. Zintzaras E, Ioannidis JP 2005; HEGESMA: Genome search meta-analysis and heterogeneity testing Bioinformatics 21:3672–3673

    Article  PubMed  CAS  Google Scholar 

  22. Higgins JP, Thompson SG, Deeks JJ, Altman DG 2003; Measuring inconsistency in meta analyses Br Med J 327:557–560

    Article  Google Scholar 

  23. Whitehead A 2002 Meta-analysis of Controlled Clinical Trials Wiley Chichester

    Google Scholar 

  24. Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers TC 1992; Cumulative meta-analysis of therapeutic trials for myocardial infarction N Engl J Med 327:248–254

    Article  PubMed  CAS  Google Scholar 

  25. Whitehead A 1997 A prospectively planned cumulative meta-analysis applied to a series of concurrent clinical trials Stat Med 16:2901–2913

    Article  PubMed  CAS  Google Scholar 

  26. Ioannidis JP, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG, 2003; Genetic associations in large versus small studies: An empirical assessment Lancet 361:567–571

    Article  PubMed  Google Scholar 

  27. Terwilliger J, Ott J, 1994 Handbook for Human Genetic Linkage Johns Hopkins University Press Baltimore

    Google Scholar 

  28. Thakkinstian A, D’Este C, Attia J 2004 Haplotype analysis of VDR gene polymorphisms: A meta analysis Osteoporos Int 5:729–734

    Google Scholar 

  29. Weir BS 1996 Genetic Data Analysis II: Methods for Discrete Population Genetic Data Sinauer Associates Sunderland, MA

    Google Scholar 

  30. Lewis PO, Zaykin D. Genetic Data Analysis: Computer Program for the Analysis of Allelic Data. Version 1.0 (d16c). Free program distributed by the authors over the internet from http://lewis.eeb.uconn.edu/lewishome/software.html

  31. Trikalinos TA, Salanti G, Khoury MJ, Ioannidis JP 2006 Impact of violations and deviations in Hardy-Weinberg equilibrium on postulated gene-disease associations Am J Epidemiol 163:300–309

    Article  PubMed  Google Scholar 

  32. Schaid DJ, Jacobsen SJ, 1999 Biased tests of association: Comparisons of allele frequencies when departing from Hardy-Weinberg proportions Am J Epidemiol 149:706–711

    PubMed  CAS  Google Scholar 

  33. Zintzaras E, Hadjigeorgiou GM 2004 Association of paraoxonase 1 gene polymorphisms with risk of Parkinson’s disease: A meta-analysis J Hum Genet 49:474–481

    Article  PubMed  Google Scholar 

  34. Zintzaras E, Stefanidis I, Santos M, Vidal F 2006; Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease? Hepatology 43:352–361

    Article  PubMed  CAS  Google Scholar 

  35. Zintzaras E, Stefanidis I 2005 Association between the GLUT1 gene polymorphism and the risk of diabetic nephropathy: A meta-analysis J Hum Genet 50:84–91

    Article  PubMed  Google Scholar 

  36. Krajinovic M, Lamothe S, Labuda D, et al. 2004 Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia Blood 103:252–257

    Article  PubMed  CAS  Google Scholar 

  37. Schnakenberg E, Mehles A, Cario G, et al. 2005; Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukaemia in a German study population BMC Med Genet 6:23

    Article  PubMed  CAS  Google Scholar 

  38. Franco RF, Simoes BP, Tone LG, Gabellini SM, Zago MA, Falcao RP 2001 The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukaemia Br J Haematol 115:616–618

    Article  PubMed  CAS  Google Scholar 

  39. Skibola CF, Smith MT, Kane E, et al. 1999; Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults Proc Natl Acad Sci USA 96:12810–12815

    Article  PubMed  CAS  Google Scholar 

  40. Chatzidakis K, Goulas A, Athanasiadou-Piperopoulou F, Fidani L, Koliouskas D, Mirtsou V. Methylenetetrahydrofolate reductase C677T polymorphism: Association with risk for childhood acute lymphoblastic leukemia and response during the initial phase of chemotherapy in Greek patients. Pediatr Blood Cancer 2005 [Epub ahead of print]

  41. Oliveira E, Alves S, Quental S, et al. 2005 The MTHFR C677T and A1298C polymorphisms and susceptibility to childhood acute lymphoblastic leukemia in Portugal J Pediatr Hematol Oncol 27:425–429

    Article  PubMed  Google Scholar 

  42. Balta G, Yuksek N, Ozyurek E, et al. 2003; Characterization of MTHFR, GSTM1, GSTT1, GSTP1, and CYPIA1 genotypes in childhood acute leukemia Am J Hematol 73:154–160

    Article  PubMed  CAS  Google Scholar 

  43. Silverman EK, Palmer LJ, 2000; Case-control association studies for the genetics of complex respiratory diseases Am J Respir Cell Mol Biol 22:645–648

    PubMed  CAS  Google Scholar 

  44. Xu J, Turner A, Little J, Bleecker ER, Meyers DA, 2002; Positive results in association studies are associated with departure from Hardy-Weinberg equilibrium: Hint for genotyping error? Hum Genet 111:573–574

    Article  PubMed  Google Scholar 

  45. Zintzaras E 2006 Methylenetetrahydrofolate reductase (MTHFR) gene and susceptibility to breast cancer: A meta-analysis Clin Genet 69: 327–336

    Article  PubMed  CAS  Google Scholar 

  46. Zintzaras E, Chatzoulis DZ, Karabatsas CH, Stefanidis I 2005 The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: A meta-analysis J Hum Genet 50:267–275

    Article  PubMed  CAS  Google Scholar 

  47. Zintzaras E. C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in schizophrenia, bipolar disorder and depression: A meta-analysis of genetic association studies. Psychiatric Genet 2006; 16: 105–115

    Google Scholar 

  48. Zintzaras E. Association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with genetic susceptibility to gastric cancer: a meta-analysis. J Hum Genet 2006 [Epub ahead of print]

  49. Egger M, Davey SG, Schneider M, Minder C 1997; Bias in meta-analysis detected by a simple, graphical test Br Med J 315:629–634

    CAS  Google Scholar 

  50. Begg CB, Mazumdar N. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088–1101

    Google Scholar 

  51. Muncer S, 2002; Response to: ‘Power dressing and meta-analysis: Incorporating power analysis into meta-analysis J Adv Nursing 38:274–280

    Article  Google Scholar 

  52. Kono S, Chen K 2005; Genetic polymorphisms of methylenetetrahydrofolate reductase and colorectal cancer and adenoma Cancer Sci 96:535–542

    Article  PubMed  CAS  Google Scholar 

  53. Lau J, Ioannidis JP, Schmid CH 1998 Summing up evidence: One answer is not always enough Lancet 351:123–127

    Article  PubMed  CAS  Google Scholar 

  54. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG, 2001; Replication validity of genetic association studies Nat Genet 29:306–309

    Article  PubMed  CAS  Google Scholar 

  55. Ioannidis JP 2003 Genetic associations: False or true? Trends Mol Med 9(4):135–138

    Article  PubMed  Google Scholar 

  56. Ioannidis JP, Trikalinos TA 2005 Early extreme contradictory estimates may appear in published research: The Proteus phenomenon in molecular genetics research and randomized trials J Clin Epidemiol 58:543–549

    Article  PubMed  Google Scholar 

  57. Skibola CF, Smith MT, Hubbard A, et al. 2002; Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia Blood 99:3786–3791

    Article  PubMed  CAS  Google Scholar 

  58. Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PF, 2002; Folic acid intake from fortification in United States exceeds predictions J Nutr 132:2792–2798

    PubMed  CAS  Google Scholar 

  59. Clayton D, McKeigue PM 2001; Epidemiological methods for studying genes and environmental factors in complex diseases Lancet 358:1356–1360

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece

    Elias Zintzaras, Theocharis Koufakis, Panayiotis D. Ziakas & Paraskevi Rodopoulou

  2. Department of Medicine Pathophysiology, University of Athens School of Medicine, Athens, Greece

    Panayiotis D. Ziakas, Stavroula Giannouli & Michael Voulgarelis

  3. Department of Biomathematics, University of Thessaly School of Medicine, Papakyriazi 22, Larissa , 41222, Greece

    Elias Zintzaras

Authors
  1. Elias Zintzaras
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Theocharis Koufakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Panayiotis D. Ziakas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paraskevi Rodopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stavroula Giannouli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Voulgarelis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elias Zintzaras.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zintzaras, E., Koufakis, T., Ziakas, P.D. et al. A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in acute lymphoblastic leukemia. Eur J Epidemiol 21, 501–510 (2006). https://doi.org/10.1007/s10654-006-9027-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10654-006-9027-8

Keywords

Search

Navigation