Confirmation of childhood acute lymphoblastic leukemia variants, ARID5B and IKZF1, and interaction with parental environmental exposures.

Tiffany-Jane Evans,John R Attia,Laurent Orsi,Sarra E Jamieson,Bente A Talseth-Palmer,Nikola A Bowden,Jérémie Rudant,Daniel Catchpoole,Jacqueline Clavel,Elizabeth Milne,Bruce K Armstrong,Denise Anderson,Nicholas H De Klerk,Rodney J Scott,Elizabeth G Holliday,Ebony Richardson,Laura Lavis,Jeffrey S Chang

doi:10.1371/journal.pone.0110255

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.

Highlights

Contemporary genome wide association studies (GWAS) have consistently revealed, in the European population, two genetic loci that are associated with childhood acute lymphoblastic leukemia (ALL) risk [1,2,3,4]
Australian Study of Childhood Acute Lymphoblastic Leukaemia (Aus-ALL) was approved by the human research ethics committees at all participating hospitals and the Hunter Community study was approved by the University of Newcastle Research Ethics Committee and the Hunter New England Health Service Research Ethics Committee
The most significantly associated SNP was rs4245595 at ARID5B where G is the risk allele, and the association was stronger for B-cell ALL

Summary

Introduction

Contemporary genome wide association studies (GWAS) have consistently revealed, in the European population, two genetic loci that are associated with childhood acute lymphoblastic leukemia (ALL) risk [1,2,3,4]. A graduated scale of ALL risk was demonstrated for: i) increasing number of risk alleles at four of the loci combined (ARID5A, IKZF1, CEBPE and BMI1-PIP4K2A); and ii) an ARID5B risk allele with odds highest for children younger than five years and lowest for those older than 10 years. This information underscores the polygenic nature of childhood ALL and places some emphasis on the potential for interaction with environmental triggers and the developmental stages at which they occur

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Results

Discussion

Conclusion