Association between Polymorphic Variation at the IL5RA Locus and the Severity of FIP1L1-PDGFRA Positive Chronic Eosinophilic Leukaemia

Abstract FIP1L1-PDGFRA is a cytogenetically cryptic fusion gene seen in a minority of patients with chronic eosinophilic leukaemia (CEL). Observations in mice have suggested that FIP1L1-PDGFRA alone is insufficient to induce all features of the human disease, and that a secondary event associated with IL-5 overexpression may be required for the full phenotype. In this study we have investigated the hypothesis that constitutional genetic variation in IL-5 signalling may be associated with the development or severity of FIP1L1-PDGFRA positive CEL in humans. We genotyped six single nucleotide polymorphisms (SNP) within or close to the IL5RA or IL5 genes in 82 European patients with FIP1L1-PDGFRA positive CEL plus, as controls, healthy individuals (n=100), patients with FIP1L1-PDGFRA negative eosinophilia (n=100) or patients with chronic myeloid leukaemia (n=100). We found no association between SNP allele frequency between FIP1L1-PDGFRA positive and control cases. However for FIP1L1-PDGFRA cases, we found an association between the genotype at rs4054760, a SNP in the 5′UTR of IL5RA, and peripheral blood eosinophil count (P=0.026) as well as the presence or absence of tissue infiltration (P=0.032). Although these associations fell below the level of significance once corrected for multiple testing, no such association was seen in FIP1L1-PDGFRA negative cases and no difference in allele frequencies for rs4054760 was seen in control populations across Europe. Furthermore, in an analysis of 128 patients with CML, there was a trend towards lower expression of IL5RA expression in cases with a c/t or t/t genotype compared to those who were c/c (P=0.08). These data suggest that the constitutional IL5RA genotype may be associated with the severity of FIP1L1-PDGFRA disease.