Genetic association with B-cell acute lymphoblastic leukemia in allogeneic transplant patients differs by age and sex

Abstract

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 [ORmeta] 5 3.7; 95% confidence interval [CI], 2.5, 6.2; P value from meta-analysis [Pmeta] 5 6.0 3 1029). The previously reported pediatric B-ALL GWAS variant, rs11980379 (IKZF1), replicated in B-ALL pediatric patients (ORmeta 5 2.3; 95% CI, 1.5, 3.7; Pmeta 5 1.0 3 1029), with evidence of heterogeneity (P 5 .02) between males and females. Sex differences in single-nucleotide polymorphism effect were seen in those .15 years (OR 5 1.7; 95% CI, 1.4, 2.2, PMales 5 6.38 3 1026/OR 5 1.1; 95% CI, 0.8, 1.5; PFemales 5 .6) but not #15 years (OR 5 2.3; 95% CI, 1.4, 3.8; PMales 5 .0007/OR 5 1.9; 95% CI, 1.2, 3.2; PFemales 5 .007). The latter association replicated in independent pediatric B-ALL cohorts. A previously identified adolescent and young-adult onset ALL-associated variant in GATA3 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 IKZF1 associations with B-ALL may be sex and age specific.