title: The severity of FIP1L1-PDGFRA-positive chronic eosinophilic leukaemia is associated with polymorphic variation at the IL5RA locus.
abstract: 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 chronic eosinophilic leukaemia (CEL) in humans. We genotyped six single-nucleotide polymorphisms (SNP) within or close to the IL5RA or IL5 genes in 82 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 (CML) (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, an 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 112 patients with CML, IL5RA expression was strongly related to rs4054760 genotype (P<0.001). These data suggest that the variations in IL5RA expression are linked to constitutional IL5RA genotype and severity of FIP1L1-PDGFRA disease.
authors.affiliation: Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, UK.
authors.forename: S
authors.initials: S
authors.lastname: Burgstaller
authors.forename: S
authors.initials: S
authors.lastname: Kreil
authors.forename: K
authors.initials: K
authors.lastname: Waghorn
authors.forename: G
authors.initials: G
authors.lastname: Metzgeroth
authors.forename: C
authors.initials: C
authors.lastname: Preudhomme
authors.forename: K
authors.initials: K
authors.lastname: Zoi
authors.forename: H
authors.initials: H
authors.lastname: White
authors.forename: D
authors.initials: D
authors.lastname: Cilloni
authors.forename: C
authors.initials: C
authors.lastname: Zoi
authors.forename: F
authors.initials: F
authors.lastname: Brito-Babapulle
authors.forename: C
authors.initials: C
authors.lastname: Walz
authors.forename: A
authors.initials: A
authors.lastname: Reiter
authors.forename: N C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D002908:Chronic Disease; D004804:Eosinophils; D005060:Europe / Q000453:epidemiology; D015973:Gene Expression Regulation, Leukemic; D005838:Genotype; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D015848:Interleukin-5 / Q000235:genetics; D053666:Interleukin-5 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D007958:Leukocyte Count; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000032:analysis* / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis* / Q000235:genetics; D039221:mRNA Cleavage and Polyadenylation Factors / Q000032:analysis* / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; C508599:IL5 protein, human; C485918:IL5RA protein, human; D015848:Interleukin-5; D053666:Interleukin-5 Receptor alpha Subunit; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D039221:mRNA Cleavage and Polyadenylation Factors; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha