title: Genetic variation in the folate metabolic pathway and risk of childhood leukemia.
abstract: Studies of childhood leukemia and the potential etiologic role of genetic variation in folate metabolism have produced conflicting findings and have often been based on small numbers. We investigated the association between polymorphisms in key folate metabolism enzymes (MTHFR 677 C>T, MTHFR 1298 A>C, SHMT1 1420 C>T, MTR 2756 A>G, TS 1494del6, and TS 28bp repeat) in 939 cases of childhood acute lymphoblastic leukemia (ALL) and 89 cases of acute myeloid leukemia (AML) recruited into the United Kingdom Childhood Cancer Study. We also examined the maternal genotypes of 752 of these cases. Data from 824 noncancer controls recruited were used for comparison. No evidence of an association with MTHFR 677 was observed for ALL or AML, either in children or their mothers. However, in children an increased risk of ALL (odds ratio [OR] = 1.88; 95% confidence interval [CI], 1.16-3.07; P = .010) and AML (OR = 2.74; 95% CI, 1.07-7.01; P = .036) was observed with the MTR 2756 GG genotype; the association was most pronounced for cases with the MLL translocation (OR = 4.90; 95% CI, 1.30-18.45; P = .019). These data suggest that genetic variation in methionine synthase could mediate risk of childhood leukemia, either via effects on DNA methylation or via effects on fetal growth and development.
authors.affiliation: Epidemiology & Genetics Unit, Department of Health Sciences, University of York, York, UK. tracy.lightfoot@egu.york.ac.uk
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Lightfoot
authors.forename: W Thomas
authors.initials: WT
authors.lastname: Johnston
authors.forename: Dan
authors.initials: D
authors.lastname: Painter
authors.forename: Jill
authors.initials: J
authors.lastname: Simpson
authors.forename: Eve
authors.initials: E
authors.lastname: Roman
authors.forename: Chris F
authors.initials: CF
authors.lastname: Skibola
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
authors.forename: James M
authors.initials: JM
authors.lastname: Allan
authors.forename: G Malcolm
authors.initials: GM
authors.lastname: Taylor
mesh_terms: D016022:Case-Control Studies; D005492:Folic Acid / Q000378:metabolism*; D014644:Genetic Variation / Q000235:genetics*; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*
chemical_list: D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); C021787:5-methylthioribose kinase