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Background  We carried out a candidate gene association study in pediatric acute lymphoblastic leukemia (ALL) to identify possible genetic risk factors in a Hungarian population.    Methods  The 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.    Results  With 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.    Conclusions  In 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.

bmc medical genomics

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