Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia
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Folate is involved in the one-carbon metabolism that plays an essential role in the synthesis, repair, and methylation of DNA. We examined whether child’s germline genetic variation in the folate pathway is associated with childhood acute lymphoblastic leukemia (ALL), and whether periconception maternal folate and alcohol intake modify the risk.
Seventy-six single nucleotide polymorphisms (SNPs), including 66 haplotype-tagging SNPs in 10 genes (CBS, DHFR, FOLH1, MTHFD1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, and TYMS), were genotyped in 377 ALL cases and 448 controls. Log-additive associations between genotypes and ALL risk were adjusted for age, sex, Hispanic ethnicity (when appropriate), and maternal race.
Single and haplotype SNPs analyses showed statistically significant associations between SNPs located in (or adjacent to) CBS, MTRR, TYMS/ENOFS, and childhood ALL. Many regions of CBS were associated with childhood ALL in Hispanics and non-Hispanics (p < 0.01). Levels of maternal folate intake modified associations with SNPs in CBS, MTRR, and TYMS.
Our data suggest the importance of genetic variability in the folate pathway and childhood ALL risk.
KeywordsCase–control study Children DNA methylation Folate Genetic polymorphisms Leukemia
This research could not have been conducted without the strong support from our clinical collaborators and participating hospitals which include: University of California Davis Medical Center (Dr. Jonathan Ducore), University of California San Francisco (Dr. Mignon Loh and Dr Katherine Matthay), Children’s Hospital of Central California (Dr. Vonda Crouse), Lucile Packard Children’s Hospital (Dr. Gary Dahl), Children’s Hospital Oakland (Dr. James Feusner), Kaiser Permanente Sacramento (Dr. Vincent Kiley), Kaiser Permanente Santa Clara (Dr. Carolyn Russo and Dr. Alan Wong), Kaiser Permanente San Francisco (Dr. Kenneth Leung), and Kaiser Permanente Oakland (Dr. Stacy Month), and the families of the study participants. We also acknowledge our collaborators at the California Department of Public Health, and the entire Northern California Childhood Leukemia Study staff for their effort and dedication. Financial support: Children With Leukemia, UK, grants 2005/027 and 2006/051; National Institute of Environmental Health Sciences, grants P42-ES04705 and R01 ES09137. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Environmental Health Sciences.
Conflict of interest
The authors declare no competing financial interests.
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