AbstractBackground: 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 × 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. Cancer Epidemiol Biomarkers Prev; 19(9); 2152–63. ©2010 AACR.