title: Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes.
abstract: Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817672) and three additional iron regulatory gene (IRG) variants (SLC11A2 rs422982; TMPRSS6 rs855791 and rs733655) for their associations with childhood ALL. Being positive for either of the HFE variants yielded a modestly elevated odds ratio (OR) for childhood ALL risk in males (1.40, 95% CI=0.83-2.35), which increased to 2.96 (95% CI=1.29-6.80) in the presence of a particular TFRC genotype for rs3817672 (P interaction=0.04). The TFRC genotype also showed an ethnicity-specific association, with increased risk observed in non-Hispanic Whites (OR=2.54, 95% CI=1.05-6.12; P interaction with ethnicity=0.02). The three additional IRG SNPs all showed individual risk associations with childhood ALL in males (OR=1.52-2.60). A polygenic model based on the number of variant alleles in five IRG SNPs revealed a linear increase in risk among males with the increasing number of variants possessed (OR=2.0 per incremental change, 95% CI=1.29-3.12; P=0.002). Our results replicated previous HFE risk associations with childhood ALL in a US population and demonstrated novel associations for IRG SNPs, thereby strengthening the hypothesis that iron excess mediated by genetic variants contributes to childhood ALL risk.
authors.affiliation: Department of Epidemiology, Robert Stempel College of Public Health & Social Work, Florida International University, 11200 SW 8th Street, AHC II 595-1, Miami, FL 33199, United States. Electronic address: akenn001@fiu.edu.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Kennedy
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, United States. Electronic address: kykamdar@txch.org.
authors.forename: Kala Y
authors.initials: KY
authors.lastname: Kamdar
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, United States. Electronic address: Philip.Lupo@bcm.edu.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Lupo
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, United States. Electronic address: mfokcu@txch.org.
authors.forename: M Fatih
authors.initials: MF
authors.lastname: Okcu
authors.affiliation: Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, United States. Electronic address: scheurer@bcm.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Scheurer
authors.affiliation: Department of Dietetics and Nutrition, Robert Stempel College of Public Health & Social Work, Florida International University, Miami, FL, United States. Electronic address: baumm@fiu.edu.
authors.forename: Marianna K
authors.initials: MK
authors.lastname: Baum
authors.affiliation: Department of Epidemiology, Robert Stempel College of Public Health & Social Work, Florida International University, 11200 SW 8th Street, AHC II 595-1, Miami, FL 33199, United States. Electronic address: dorakm@hope.ac.uk.
authors.forename: M Tevfik
authors.initials: MT
authors.lastname: Dorak
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007223:Infant; D035925:Iron-Regulatory Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000453:epidemiology / Q000235:genetics*; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D035925:Iron-Regulatory Proteins; D008565:Membrane Proteins
keywords: Childhood leukemia; Genetic predisposition to disease; Iron homeostasis; Iron regulatory gene markers