This meta-analysis showed that both short-term and long-term breastfeeding reduced the risk of childhood ALL and AML, suggesting that the protective effect of breastfeeding might not be limited to ALL as earlier hypothesized. Potential bias introduced by different participation rates for case and control samples that differed in SES can be minimized by implementing larger case-control studies with SES-matched, population-based controls.
Objective
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.
Methods
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.
Results
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.
Conclusion
Our data suggest the importance of genetic variability in the folate pathway and childhood ALL risk.
Background
Childhood acute lymphoblastic leukemia (ALL) has been hypothesized to have an infection and immune-related etiology. The lack of immune priming in early childhood may result in abnormal immune responses to infections later in life and increase ALL risk.
Methods
The current analyses examined the association between childhood ALL and 208 single nucleotide polymorphisms (SNPs) of 29 adaptive immune function genes among 377 ALL cases and 448 healthy controls. Single SNPs were analyzed with a log-additive approach using logistic regression models adjusted for sex, age, Hispanic ethnicity, and race. Sliding window haplotype analyses were performed with haplotypes consisting of 2 to 6 SNPs.
Results
Of the 208 SNPs, only rs583911 of IL12A, which encodes a critical modulator of T-cell development, remained significant after accounting for multiple testing (odds ratio for each copy of the variant G allele = 1.52, 95% confidence interval: 1.25–1.85, p = 2.9 × 10−5). This increased risk was stronger among first-born children of all ethnicities and among non-Hispanic children with less daycare attendance, consistent with the hypothesis regarding the role of early immune modulation in the development of childhood ALL. Haplotype analyses identified additional regions of CD28, FCGR2, GATA3, IL2RA, STAT4, and STAT6 associated with childhood ALL.
Conclusion
Polymorphisms of genes on the adaptive immunity pathway are associated with childhood ALL risk.
Impact
Results of this study support an immune-related etiology of childhood ALL. Further confirmation is required to detect functional variants in the significant genomic regions identified in this study, in particular for IL12A.
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