AbstractThe 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 IL13_rs1295686A/A genotype had an increased risk of AML (P_Corr = 0.0144) whereas carriers of the VEGFA_rs25648T allele had a decreased risk of developing the disease (P_Corr = 0.00086). In addition, we found an association of the IL8_rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (P_Corr = 0.072). Functional experiments suggested that the effect of the IL13_rs1295686 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 IL8_rs2227307 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.