Folic acid supplementation, MTHFR and MTRR polymorphisms, and the risk of childhood leukemia: the ESCALE study (SFCE).
OBJECTIVE
Fetal folate deficiency may increase the risk of subsequent childhood acute leukemia (AL), since folates are required for DNA methylation, synthesis, and repair, but the literature remains scarce. This study tested the hypothesis that maternal folic acid supplementation before or during pregnancy reduces AL risk, accounting for the SNPs rs1801133 (C677T) and rs1801131 (A1298C) in MTHFR and rs1801394 (A66G) and rs1532268 (C524T) in MTRR, assumed to modify folate metabolism.


METHODS
The nationwide registry-based case-control study, ESCALE, carried out in 2003-2004, included 764 AL cases and 1,681 controls frequency matched with the cases on age and gender. Information on folic acid supplementation was obtained by standardized telephone interview. The genotypes were obtained using high-throughput platforms and imputation for untyped polymorphisms. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders.


RESULTS
AL was significantly inversely associated with maternal folic acid supplementation before and during pregnancy (OR = 0.4; 95 % confidence interval: [0.3-0.6]). MTHFR and MTRR genetic polymorphisms were not associated with AL. However, AL was positively associated with homozygosity for any of the MTHFR polymorphisms and carriership of both MTRR variant alleles (OR = 1.6 [0.9-3.1]). No interaction was observed between MTHFR, MTRR, and maternal folate supplementation.


CONCLUSIONS
The study findings support the hypothesis that maternal folic acid supplementation may reduce the risk of childhood AL. The findings also suggest that the genotype homozygous for any of the MTHFR variants and carrying both MTRR variants could be a risk factor for AL.
Environmental Epidemiology of Cancer, INSERM U1018, Villejuif, France. alicia.amigou@inserm.fr
Alicia
A
Amigou
Jérémie
J
Rudant
Laurent
L
Orsi
Stéphanie
S
Goujon-Bellec
Guy
G
Leverger
André
A
Baruchel
Yves
Y
Bertrand
Brigitte
B
Nelken
Geneviève
G
Plat
Gérard
G
Michel
Stéphanie
S
Haouy
Pascal
P
Chastagner
Stéphane
S
Ducassou
Xavier
X
Rialland
Denis
D
Hémon
Jacqueline
J
Clavel
D016022:Case-Control Studies; D002675:Child, Preschool; D019587:Dietary Supplements; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005492:Folic Acid / Q000008:administration & dosage*; D005494:Folic Acid Deficiency / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*
D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)