Folate metabolic gene polymorphisms and childhood acute lymphoblastic leukemia: a case-control study

We genotyped six folate metabolic pathway genes for 11 polymorphisms in 460 cases of childhood acute lymphoblastic leukemia ( ALL) and 552 ethnically matched controls. None of the polymorphisms except the 66A > G (122M) in the 5-methyl-tetrahydrofolate-homocysteine methyltransferase reductase ( MTRR) gene showed any effect on disease risk. The carriers of the G-allele were associated with a marginal decreased risk of ALL ( gender-adjusted global P = 0.03; multiple-testing corrected P = 0.25). Analysis of four polymorphisms in the MTRR gene showed statistically significant differences in haplotype distribution between cases and controls ( global P < 0.0001). The haplotypes GCAC ( odds ratio ( OR) 0.5, 95% confidence interval (CI) 0.4-0.6) and ATAC ( OR 0.5, 95% CI 0.3-0.6) were associated with a reduced risk and the haplotypes ACAC ( OR 2.3, 95% CI 1.8-2.9) and GTAC ( OR 1.8, 95% CI 1.4-2.3) with an increased risk. The genotype-combination analyses indicated that the best model stratifies cases and controls based on the 66A > G and the 524C > T polymorphisms in the MTRR gene ( global P 0.03). Our results suggest that, besides a weak association of childhood ALL with the 66A > G polymorphism, haplotypes within the MTRR gene may, in part, account for population-based differences in risk.