Evaluating genetic mechanisms for risk of childhood acute lymphoblastic leukemia among Hispanics

Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) than other races/ethnicities, but more work is needed to better understand genetic susceptibility in this population. Genome-wide association studies (GWAS) of childhood acute lymphoblastic leukemia (ALL) to date have focused on inherited genetic effects; however, maternal genetic effects (the role of maternal genotype on disease susceptibility of offspring) and imprinting effects (where gene expression is altered depending on whether the risk allele was inherited from the father or the mother) could also play a role in ALL susceptibility. We conducted a genome-wide association study (GWAS) of childhood B-cell ALL (B-ALL) among Hispanics to confirm and identify variants associated with disease risk in this population, as well as to evaluate maternal genetic effects and genomic imprinting effects among this ethnic group. We utilized a case-parent trio study design, which is immune to population stratification bias, a potential limitation of case-control studies evaluating ethnically diverse populations such as Hispanics. ^ Using 522 individuals from 231 families, we confirmed two inherited SNPs in ARID5B associated with childhood B-ALL (rs7089424, RR=2.23, 95% CI=1.55-3.22, p=5.05×10-6, and rs10821936, RR=2.31, 95% CI=1.59-3.34, p=2.6×10-6). In addition, a novel variant with near-genome-wide significance was identified at 17q12 (rs4430796 on HNF1B, RR=0.51, 95% CI=0.37-0.69, p=1.29×10-5) in a combined analysis of the discovery cohort and an independent replication cohort. We also identified a novel maternal genotype associated with childhood B-ALL at 11q13.2-q13.3 (rs12365708, MTL5) in both the discovery cohort (RR=3.24, 95% CI=1.83-5.75, p=4.27×10-6) and the combined population (RR=3.25, 95% CI=1.90-5.57, p=8.78×10-7). ^ This study is the first family-based GWAS to evaluate inherited genetic variation associated with childhood ALL within a Hispanic population, as well as the first GWAS to investigate maternal genotype effects associated with childhood B-ALL. These results add to the body of knowledge about genetic risk factors of ALL for Hispanics, a group at higher risk of this disease. Furthermore, our results suggest that examining maternal genetic effects may be important in gaining a better understanding of the genetic risk factors for childhood B-ALL.