Genetic variants in ARID5B and CEBPE are childhood ALL susceptibility loci in Hispanics

Abstract

Recent genome-wide studies conducted in European Whites have identified novel susceptibility genes for childhood acute lymphoblastic leukemia (ALL). We sought to examine whether these loci are susceptibility genes among Hispanics, whose reported incidence of childhood ALL is the highest of all ethnic groups in California, and whether their effects differ between Hispanics and non-Hispanic Whites (NHWs). We genotyped 13 variants in these genes among 706 Hispanic (300 cases, 406 controls) and 594 NHW (225 cases, 369 controls) participants in a matched population-based case–control study in California. We found significant associations for the five studied ARID5B variants in both Hispanics (p values of 1.0 × 10−9 to 0.004) and NHWs (p values of 2.2 × 10−6 to 0.018). Risk estimates were in the same direction in both groups (ORs of 1.53–1.99 and 1.37–1.84, respectively) and strengthened when restricted to B-cell precursor high-hyperdiploid ALL (>50 chromosomes; ORs of 2.21–3.22 and 1.67–2.71, respectively). Similar results were observed for the single CEBPE variant. Hispanics and NHWs exhibited different susceptibility loci at CDKN2A. Although IKZF1 loci showed significant susceptibility effects among NHWs (p < 1 × 10−5), their effects among Hispanics were in the same direction but nonsignificant, despite similar minor allele frequencies. Future studies should examine whether the observed effects vary by environmental, immunological, or lifestyle factors.

Genetic Markers, Birth Characteristics, and Childhood Leukemia Risk

“…Most GWAS, until recently, have identified risk loci using only European-origin populations. Variant polymorphisms located within the ARID5B, IKZF1, and CEBPE genes have reported strong risk associations in multiple GWAS [34][35][36][37][55][56][57]. Our study provides some confirmation of previously discovered genetic markers associated with childhood ALL, which also validated our case-control set for further exploration.…”

“…The study population only included 32 childhood ALL patients, of which 14 were male, and did not find any significant results. Other hematologic malignancies studies on acute myeloid leukemia [56] and Hodgkin disease [32] have found no risk associations with HFE variants, and a myelodysplastic syndrome study [57] revealed a positive association, which was not been replicated in a different population sample [58].…”

“…The SNP rs4132601, located in the Ikaros family zinc finger 1 (IKZF1) gene, is associated with increased risk of childhood ALL in multiple studies [34,36,56,57,59]. …”

“…One study found this variant to be a significant risk marker amongst non-Hispanic Whites, but not in Hispanics, despite similar allele frequencies [57]. Chokkalingam et al hypothesized that that this marker's association may be due to linkage disequilibrium with a functional variant, and because of admixture in Hispanic populations the linkage disequilibrium may vary [57]. Our study was unable to examine this SNP, due to Hardy-Weinberg disequilibrium found in controls, even after stratification for race/ethnicity.…”

Evaluating the Role of Admixture in Cancer Therapy Via in Vitro Drug Response and Multivariate Genome-Wide Associations

“…To this point, the well-described [11] higher rates of relapse and poorer survival of Hispanic children with acute lymphoblastic leukemia (ALL) have recently been linked to percentage of Native American ancestry using principal component analysis (PCA) [12]. Furthermore, genomewide association studies (GWASs) have linked polymorphisms in the ARID5B gene to both elevated risk of developing ALL and risk of relapse after multiagent chemotherapy in this population [13,14]. Despite these advances, whether these genetic associations are responsible for variations in response to particular antineoplastic agents remains unclear.…”