Genetic Association with B-cell Acute Lymphoblastic Leukemia in Allogeneic Transplant Patients Differs by Age and Sex

The incidence and mortality rates of B-cell acute lymphoblastic leukemia (B-ALL) differ by age and sex. To determine if inherited genetic susceptibility contributes to these differences we performed 2 genome-wide association studies (GWAS) by age, sex, and subtype and subsequent meta-analyses. The GWAS included 446 B-ALL cases, and 3027 healthy unrelated blood and marrow transplant (BMT) donors as controls from the Determining the Influence of Susceptibility Conveying Variants Related to One-Year Mortality after BMT (DISCOVeRY-BMT) study. We identified 1 novel variant, rs189434316, significantly associated with odds of normal cytogenetic B-ALL (odds ratio from meta-analysis [OR] = 3.7; 95% confidence interval [CI], 2.5, 6.2; value from meta-analysis [] = 6.0 × 10). The previously reported pediatric B-ALL GWAS variant, rs11980379 (), replicated in B-ALL pediatric patients (OR = 2.3; 95% CI, 1.5, 3.7; = 1.0 × 10), with evidence of heterogeneity ( = .02) between males and females. Sex differences in single-nucleotide polymorphism effect were seen in those >15 years (OR = 1.7; 95% CI, 1.4, 2.2, = 6.38 × 10/OR = 1.1; 95% CI, 0.8, 1.5; = .6) but not ≤15 years (OR = 2.3; 95% CI, 1.4, 3.8; = .0007/OR = 1.9; 95% CI, 1.2, 3.2; = .007). The latter association replicated in independent pediatric B-ALL cohorts. A previously identified adolescent and young-adult onset ALL-associated variant in is associated with B-ALL risk in those >40 years. Our findings provide more evidence of the influence of genetics on B-ALL age of onset and we have shown the first evidence that associations with B-ALL may be sex and age specific.