Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia.

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.

Breastfeeding and the risk of childhood leukemia: a meta-analysis.

OBJECTIVE: The authors used a meta-analytic technique to (1) quantify the evidence of an association between duration of breastfeeding and risk of childhood acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML), (2) assess the influence of socioeconomic status (SES) on any such associations, and (3) discuss the implications of these findings for the evaluation of whether breastfeeding reduces the risk of childhood leukemia. METHODS: A fixed effects model was employed to systematically combine the results of 14 case-control studies addressing the effect of short-term (< or = 6 months) and long-term (>6 months) breastfeeding on the risk of childhood ALL and/or AML. Subgroup analyses of studies that did and did not adjust for SES were also performed. RESULTS: A significant, negative association was observed between long-term breastfeeding and both ALL risk (odds ratio [OR]=0.76; 95% confidence interval [CI] 0.68, 0.84) and AML risk (OR=0.85; 95% CI 0.73, 0.98). Short-term breastfeeding was similarly protective for ALL and AML. Results for studies that adjusted and did not adjust for SES were not significantly different from the results for the 14 studies combined. CONCLUSIONS: 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.

Genetic polymorphisms in adaptive immunity genes and childhood acute lymphoblastic leukemia.

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 (SNP) 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 done 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 x 10(-5)). This increased risk was stronger among firstborn children of all ethnicities and among non-Hispanic children with less day care attendance, consistent with the hypothesis about 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.