title: Using a Bayesian hierarchical model for identifying single nucleotide polymorphisms associated with childhood acute lymphoblastic leukemia risk in case-parent triads.
abstract: Childhood acute lymphoblastic leukemia (ALL) is a condition that arises from complex etiologies. The absence of consistent environmental risk factors and the presence of modest familial associations suggest ALL is a complex trait with an underlying genetic component. The identification of genetic factors associated with disease is complicated by complex genetic covariance structures and multiple testing issues. Both issues can be resolved with appropriate Bayesian variable selection methods. The present study was undertaken to extend our hierarchical Bayesian model for case-parent triads to incorporate single nucleotide polymorphisms (SNPs) and incorporate the biological grouping of SNPs within genes. Based on previous evidence that genetic variation in the folate metabolic pathway influences ALL risk, we evaluated 128 tagging SNPs in 16 folate metabolic genes among 118 ALL case-parent triads recruited from the Texas Children's Cancer Center (Houston, TX) between 2003 and 2010. We used stochastic search gene suggestion (SSGS) in hierarchical Bayesian models to evaluate the association between folate metabolic SNPs and ALL. Using Bayes factors among these variants in childhood ALL case-parent triads, two SNPs were identified with a Bayes factor greater than 1. There was evidence that the minor alleles of NOS3 rs3918186 (OR = 2.16; 95% CI: 1.51-3.15) and SLC19A1 rs1051266 (OR = 2.07; 95% CI: 1.25-3.46) were positively associated with childhood ALL. Our findings are suggestive of the role of inherited genetic variation in the folate metabolic pathway on childhood ALL risk, and they also suggest the utility of Bayesian variable selection methods in the context of case-parent triads for evaluating the role of SNPs on disease risk.
authors.affiliation: Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Lupo
authors.affiliation: Division of Biostatistics, The University of Texas School of Public Health, Houston, Texas, United States of America.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Swartz
authors.affiliation: Division of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas School of Public Health, Houston, Texas, United States of America.
authors.forename: Darryl
authors.initials: D
authors.lastname: Nousome
authors.affiliation: Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Scheurer
mesh_terms: D001499:Bayes Theorem; D005492:Folic Acid / Q000378:metabolism; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008957:Models, Genetic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D058978:Reduced Folate Carrier Protein / Q000235:genetics*; D013781:Texas
chemical_list: D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D005492:Folic Acid; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III