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.
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References
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
Sinnett D, Krajinovic M, Labuda D, 2000 Genetic susceptibility to childhood acute lymphoblastic leukemia Leuk Lymphoma 38:447–462
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
Robien K, Ulrich CM 2003 5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: aHuGE minireview Am J Epidemiol 157:571–582
Duthie SJ, McMillan P 1997 Uracil misincorporation in human DNA detected using single cell gel electrophoresis Carcinogenesis 18:1709–1714
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
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
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
Botto LD, Yang Q 2000 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A HuGE review Am J Epidemiol 151:862–877
Selhub J 1999 Homocysteine metabolism Annu Rev Nutr 19:217–246
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
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
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
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
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
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
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
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
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
Zintzaras E, Ioannidis JP 2004; Heterogeneity testing in meta-analysis of genome searches Genet Epidemiol 24:1–15
Zintzaras E, Ioannidis JP 2005; HEGESMA: Genome search meta-analysis and heterogeneity testing Bioinformatics 21:3672–3673
Higgins JP, Thompson SG, Deeks JJ, Altman DG 2003; Measuring inconsistency in meta analyses Br Med J 327:557–560
Whitehead A 2002 Meta-analysis of Controlled Clinical Trials Wiley Chichester
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
Whitehead A 1997 A prospectively planned cumulative meta-analysis applied to a series of concurrent clinical trials Stat Med 16:2901–2913
Ioannidis JP, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG, 2003; Genetic associations in large versus small studies: An empirical assessment Lancet 361:567–571
Terwilliger J, Ott J, 1994 Handbook for Human Genetic Linkage Johns Hopkins University Press Baltimore
Thakkinstian A, D’Este C, Attia J 2004 Haplotype analysis of VDR gene polymorphisms: A meta analysis Osteoporos Int 5:729–734
Weir BS 1996 Genetic Data Analysis II: Methods for Discrete Population Genetic Data Sinauer Associates Sunderland, MA
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
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
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
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
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
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
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
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
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
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
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]
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
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
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
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
Zintzaras E 2006 Methylenetetrahydrofolate reductase (MTHFR) gene and susceptibility to breast cancer: A meta-analysis Clin Genet 69: 327–336
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
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
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]
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
Begg CB, Mazumdar N. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088–1101
Muncer S, 2002; Response to: ‘Power dressing and meta-analysis: Incorporating power analysis into meta-analysis J Adv Nursing 38:274–280
Kono S, Chen K 2005; Genetic polymorphisms of methylenetetrahydrofolate reductase and colorectal cancer and adenoma Cancer Sci 96:535–542
Lau J, Ioannidis JP, Schmid CH 1998 Summing up evidence: One answer is not always enough Lancet 351:123–127
Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG, 2001; Replication validity of genetic association studies Nat Genet 29:306–309
Ioannidis JP 2003 Genetic associations: False or true? Trends Mol Med 9(4):135–138
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
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
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
Clayton D, McKeigue PM 2001; Epidemiological methods for studying genes and environmental factors in complex diseases Lancet 358:1356–1360
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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
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DOI: https://doi.org/10.1007/s10654-006-9027-8