Early life exposure to infections and human leukocyte antigen (HLA) -DP genetic variation in the risk of childhood acute lymphoblastic leukemia

There is growing evidence supporting a role for infections and immunologic mechanisms in the etiology of childhood leukemia, particularly acute lymphoblastic leukemia (ALL). Day care attendance, birth order, and reported childhood infections are considered strong indicators of the increased likelihood of early exposure to infections. The role of early life exposures to infections and human leukocyte antigen (HLA)-DP genetic variation in the risk of childhood ALL was examined within the Northern California Childhood Leukemia Study (NCCLS).;A meta-analysis based on the results of 14 studies showed consistency and strong evidence of an association between day care attendance and a reduced risk of childhood ALL [odds ratio (OR)=0.76, 95% confidence interval (CI)=0.67, 0.87]. In multivariable analyses conducted within the NCCLS, a reduced risk of childhood ALL in non-Hispanic White children was associated with the three measures of exposure to infections, increasing day care child-hours (OR=0.83, 95% CI=0.73, 0.94), having an older sibling (OR=0.59, 95% CI=0.43, 0.83), and ear infections (OR=0.44, 95% CI=0.19, 1.02), with no evidence of multiplicative interaction. There was a strong independent effect associated with ear infections in Hispanic children (OR=0.45, 95% CI=0.25, 0.79), but not for day care attendance and birth order.;Analysis of HLA-DPB1 genetic variation does not support previous findings reported through a large United Kingdom study, but provided evidence of a possible DPI supertype association with high-hyperdiploid ALL (OR=1.96, 95% CI=1.17-3.28). When DP supertypes were examined stratified by whether or not the child has an older sibling, the DPI supertype was associated with an increased risk of ALL among children with no older sibling (OR=2.34, 95% CI=1.15, 4.77). Statistically significant multiplicative interaction was found between DPI and having an older sibling in the risk of childhood ALL (ORinteraction=0.33, 95% CI=0.13, 0.87; p-value=0.026). These results suggest that HLA-DPB1 genetic variation may confer susceptibility to childhood ALL in a subset of children that were likely to have had fewer exposures to infections as measured by presence or absence of an older sibling. This study provides additional evidence of an immune-related etiology of childhood ALL, specifically demonstrating a role for the HLA-DPBI gene jointly with early life exposures to infections.