Abstract
Genome-wide association studies (GWAS) have identified that frequent polymorphisms in ARID5B and IKZF1, two genes involved in lymphoid differentiation, increase the risk of childhood acute lymphoblastic leukemia (ALL). These findings markedly modified the current field of research on the etiology of ALL. In this new context, the present exploratory study investigated the possible interactions between these at-risk alleles and the non-genetic suspected ALL risk factors that were of sufficient prevalence in the French ESCALE study: maternal use of home insecticides during pregnancy, preconception paternal smoking, and some proxies for early immune modulation, i.e. breastfeeding, history of common infections before age one year, and birth order. The analyses were based on 434 ALL cases and 442 controls of European origin, drawn from the nationwide population-based case-control study ESCALE. Information on non-genetic factors was obtained by standardized telephone interview. Interactions between rs10740055 in ARID5B or rs4132601 in IKZF1 and each of the suspected non-genetic factors were tested, with the SNPs coded as counts of minor alleles (trend variable). Statistical interactions were observed between rs4132601 and maternal insecticide use (p = 0.012), breastfeeding p = 0.017) and repeated early common infections (p = 0.0070), with allelic odds ratios (OR) which were only increased among the children not exposed to insecticides (OR = 1.8, 95%CI: 1.3, 2.4), those who had been breastfed (OR = 1.8, 95%CI: 1.3, 2.5) and those who had had repeated early common infections (OR = 2.4, 95%CI: 1.5, 3.8). The allelic ORs were close to one among children exposed to insecticides, who had not been breastfed and who had had no or few common infections. Repeated early common infections interacted with rs10740055 (p = 0.018) in the case-only design. Further studies are needed to evaluate whether these observations of a modification of the effect of the at-risk alleles by non-genetic factors are chance findings or reflect true underlying mechanisms.
Highlights
Acute lymphoblastic leukemia [ALL] accounts for 80% of all childhood leukemia and for approximately one quarter of all childhood neoplasms in developed countries [1]
The exploratory study reported investigated the potential interactions between polymorphisms rs10740055 of ARID5B, and rs4132601 of IKZF1, and the non-genetic suspected ALL risk factors that were of sufficient prevalence in the ESCALE case-control study, for power reasons: maternal use of home insecticides during pregnancy, preconception paternal smoking, and some proxies for early immune modulation, i.e breastfeeding, history of repeated common infections before age one year, and birth order [29,30,31]
In recent years some IKZF1 and ARID5B Single Nucleotide Polymorphisms (SNP) have been shown to be clearly associated with childhood ALL
Summary
Acute lymphoblastic leukemia [ALL] accounts for 80% of all childhood leukemia and for approximately one quarter of all childhood neoplasms in developed countries [1]. The two loci associated with the greater ALL risk are in the AT-rich interactive domain 5b gene (ARID5B, chromosomal region 10q21.2) and Ikaros family zinc finger 1 gene (IKZF1, chromosomal region 7p12.21). IKZF1 codes for a zinc finger transcription factor, Ikaros, which is a key regulator of hematopoiesis. Ikaros is required for the development of the earliest B-cell progenitors and at later stages for V(D)J recombination and B-cell receptor expression [13,14]. Ikaros acts as a tumor suppressor [15] and genetic alteration of IKZF1 in leukemia cells is associated with a poor outcome in B-cell-progenitor ALL [16,17]. ARID5B is a member of the AT-rich interaction domain family of transcription factors that plays an important role in embryogenesis and growth regulation [18]. A role is supported by data from homozygous knockout mice that had immune abnormalities and reduced numbers of B-cell progenitors [19]
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