Candidate gene association study in pediatric acute lymphoblastic leukemia evaluated by Bayesian network based Bayesian multilevel analysis of relevance

Abstract

BackgroundWe carried out a candidate gene association study in pediatric acute lymphoblastic leukemia (ALL) to identify possible genetic risk factors in a Hungarian population.MethodsThe results were evaluated with traditional statistical methods and with our newly developed Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method. We collected genomic DNA and clinical data from 543 children, who underwent chemotherapy due to ALL, and 529 healthy controls. Altogether 66 single nucleotide polymorphisms (SNPs) in 19 candidate genes were genotyped.ResultsWith logistic regression, we identified 6 SNPs in the ARID5B and IKZF1 genes associated with increased risk to B-cell ALL, and two SNPs in the STAT3 gene, which decreased the risk to hyperdiploid ALL. Because the associated SNPs were in linkage in each gene, these associations corresponded to one signal per gene. The odds ratio (OR) associated with the tag SNPs were: OR = 1.69, P = 2.22x10-7 for rs4132601 (IKZF1), OR = 1.53, P = 1.95x10-5 for rs10821936 (ARID5B) and OR = 0.64, P = 2.32x10-4 for rs12949918 (STAT3). With the BN-BMLA we confirmed the findings of the frequentist-based method and received additional information about the nature of the relations between the SNPs and the disease. E.g. the rs10821936 in ARID5B and rs17405722 in STAT3 showed a weak interaction, and in case of T-cell lineage sample group, the gender showed a weak interaction with three SNPs in three genes. In the hyperdiploid patient group the BN-BMLA detected a strong interaction among SNPs in the NOTCH1, STAT1, STAT3 and BCL2 genes. Evaluating the survival rate of the patients with ALL, the BN-BMLA showed that besides risk groups and subtypes, genetic variations in the BAX and CEBPA genes might also influence the probability of survival of the patients.ConclusionsIn the present study we confirmed the roles of genetic variations in ARID5B and IKZF1 in the susceptibility to B-cell ALL. With the newly developed BN-BMLA method several gene-gene, gene-phenotype and phenotype-phenotype connections were revealed. We showed several advantageous features of the new method, and suggested that in gene association studies the BN-BMLA might be a useful supplementary to the traditional frequentist-based statistical method.

Genetic markers in a multi-ethnic sample for childhood acute lymphoblastic leukemia risk

“…The SNP rs4132601, located in the Ikaros family zinc finger 1 (IKZF1) gene, is associated with increased risk of childhood ALL in multiple studies [19,21,39,40,42]. The Ikaros proteins are known to be involved with lymphocyte development and differentiation [19], and deletions are frequent and associated with unfavorable prognosis in B-cell precursor ALL [19,43].…”

Genetic polymorphism at BCL2 as a predictor for rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone efficacy in patients with diffuse large B-cell lymphoma

“…Some studies reported associations of these SNPS with other biological outcomes and human disorders. [12][13][14][15] Rs7226979 is significantly associated with the risk of non-obstructive azoospermia.…”

Genetic Markers, Birth Characteristics, and Childhood Leukemia Risk

“…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]. …”

“…Cell studies have shown that B-lymphoid cell lines that are homozygous for the C282Y variant demonstrate greater iron uptake and increased cell sensitivity to oxidative stress [59]. The increase in oxidative stress due to the high iron levels may increase radiation sensitivity, which has been shown to increase cancer susceptibility [60,61].…”

“…during development may explain the risk [59]. Cell studies have shown that B-lymphoid cell lines that are homozygous for the C282Y variant demonstrate greater iron uptake and increased cell sensitivity to oxidative stress [59].…”