title: Confirmation of childhood acute lymphoblastic leukemia variants, ARID5B and IKZF1, and interaction with parental environmental exposures.
abstract: Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child's sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38-1.93, P = 2.13×10(-9)), and IKZF1 rs1110701 (OR 1.69, CI 1.42-2.02, p = 7.26×10(-9)). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements.
authors.affiliation: Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Tiffany-Jane
authors.initials: TJ
authors.lastname: Evans
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Milne
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Denise
authors.initials: D
authors.lastname: Anderson
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: de Klerk
authors.affiliation: Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Sarra E
authors.initials: SE
authors.lastname: Jamieson
authors.affiliation: Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Bente A
authors.initials: BA
authors.lastname: Talseth-Palmer
authors.affiliation: Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Nikola A
authors.initials: NA
authors.lastname: Bowden
authors.affiliation: Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia; Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Holliday
authors.affiliation: INSERM, U1018, Department of Environmental Epidemiology of Cancers, Villejuif, France; Paris-Sud University, UMR-S1018, Department of Environmental Epidemiology of Cancers, Research Center in Epidemiology and Population Health, Villejuif, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Rudant
authors.affiliation: INSERM, U1018, Department of Environmental Epidemiology of Cancers, Villejuif, France; Paris-Sud University, UMR-S1018, Department of Environmental Epidemiology of Cancers, Research Center in Epidemiology and Population Health, Villejuif, France; French National Registry of Childhood Blood Malignancies (RNHE), Villejuif, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Orsi
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Ebony
authors.initials: E
authors.lastname: Richardson
authors.affiliation: School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Lavis
authors.affiliation: The Tumour Bank, The Children's Cancer Research Unit, The Children's Hospital Westmead, Westmead, New South Wales, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Catchpoole
authors.affiliation: Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia; Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia; Department of Medicine, John Hunter Hospital and Hunter Medical Research Institute, New Lambton, New South Wales, Australia.
authors.forename: John R
authors.initials: JR
authors.lastname: Attia
authors.affiliation: School of Public Health, The University of Sydney and Sax Institute, Sydney, New South Wales, Australia.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Armstrong
authors.affiliation: INSERM, U1018, Department of Environmental Epidemiology of Cancers, Villejuif, France; Paris-Sud University, UMR-S1018, Department of Environmental Epidemiology of Cancers, Research Center in Epidemiology and Population Health, Villejuif, France; French National Registry of Childhood Blood Malignancies (RNHE), Villejuif, France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Clavel
authors.affiliation: Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales, Australia; Molecular Genetics, Hunter Area Pathology Service, Newcastle, New South Wales, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
mesh_terms: D000328:Adult; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D004781:Environmental Exposure; D005260:Female; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D008297:Male; D010290:Parents; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C503805:ARID5B protein, human; D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; D014157:Transcription Factors; D051740:Ikaros Transcription Factor