Abstract
The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.
Highlights
Introduction Acute MyeloidLeukaemia (AML) is a common haematological malignancy characterised by the clonal transformation of haematopoietic precursors that alter normal hematopoietic cell growth and differentiation[1]
Considering the aspects detailed above, the purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate whether 27 single nucleotide polymorphisms (SNPs) within the Interleukin 4 (IL4), Interleukin 8 (IL8), IL8RB (CXCR2), Interleukin 12 alpha (IL12A), Interleukin 12 beta (IL12B), Interleukin 13 (IL13), IFNG, IFNGR2, chemokine receptor type 5 (CCR5), migration inhibitory factor (MIF) and VEGFA loci influence the risk of developing AML
Even though only the association of the VEGFArs25648 SNP with a decreased risk of developing AML remained significant after correction for multiple testing in the discovery cohort (PCorr = 0.0014), we found that the association of IL8rs2227307 and IL13rs1295686 with AML risk was confirmed in the replication population (ORDom = 0.74, P = 0.040 and ORDom = 2.24, P = 0.0051, respectively; Table 3)
Summary
Introduction Acute MyeloidLeukaemia (AML) is a common haematological malignancy characterised by the clonal transformation of haematopoietic precursors that alter normal hematopoietic cell growth and differentiation[1]. Epidemiological studies suggested that AML onset can be patients (~ 45%) have a normal karyotype, which suggests that additional genetic alterations are needed to develop the disease. Discovery Population (n = 2027) 338 AML cases and 1689 healthy controls. Replication Population (n = 2104) 316 AML cases and 1788 healthy controls. Overall Population (n = 4131) 654 AML cases and 3477 healthy controls. AML cases Age (years) Sex ratio (male/female) Country of origin Spain Germany Italy Austria Presentation de novo (n, %) Secondary (n, %) Healthy controls Age (years)* Sex ratio (male/female) Country of origin Spain Germany Italy Austria. A set of 99 patients (39 and 61 from the discovery and replication cohorts, respectively) could not be classified according to the FAB classification. AML acute myeloid leukaemia *Age was not available in a set of German controls included in the discovery (n = 1000) and replication cohorts (n = 1068)
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