title: A polymorphism affecting MYB binding within the promoter of the PDCD4 gene is associated with severe asthma in children.
abstract: A previous genome-wide association study in asthma revealed putative associations that merit further investigation. In this study, the genome-wide significant associations of SNPs at the 5% false discovery rate were examined in independent groups of severe asthmatics. The panel consisted of 397 severe asthmatic adults, 116 severe asthmatic children, and a collection of 207 family-trios with an asthmatic proband. Three SNPs in the PDCD4 gene (rs6585018:G>A, rs1322997:C>A, and rs34104444:G>A) were significantly associated with severe childhood asthma (P values: 0.003, 0.002, 0.004) and total immunoglobulin E (IgE) levels (P values: 0.034, 0.041, 0.052). In an independent group of 234 asthmatic children and 652 controls, PDCD4 SNPs rs1407696:T>G and rs11195360:T>C were associated with total IgE levels (P values: 0.006, 0.014). In silico analysis of PDCD4 locus showed that rs6585018:G>A had the potential to affect MYB transcription factor binding, shown to act as a PDCD4-transcription inducer. Electromobility shift assays and reporter assays revealed that rs6585018:G>A alters MYB binding thereby influencing the expression of PDCD4. SNPs within MYB itself confer susceptibility to eosinophilia and asthma. Our association between a variant MYB binding site in PDCD4 and the severest form of childhood asthma therefore suggests that PDCD4 is a novel molecule of importance to asthmatic inflammatory responses.
authors.affiliation: Molecular Genetics and Genomics Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom. aristea.binia@rdls.nestle.com
authors.forename: Aristea
authors.initials: A
authors.lastname: Binia
authors.forename: Nicole
authors.initials: N
authors.lastname: Van Stiphout
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.forename: Sven
authors.initials: S
authors.lastname: Michel
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Bhavsar
authors.forename: K
authors.initials: K
authors.lastname: Fan Chung
authors.forename: Chris E
authors.initials: CE
authors.lastname: Brightling
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.forename: Andrew
authors.initials: A
authors.lastname: Bush
authors.forename: William O C
authors.initials: WO
authors.lastname: Cookson
authors.forename: Miriam F
authors.initials: MF
authors.lastname: Moffatt
mesh_terms: D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001249:Asthma / Q000235:genetics*; D001665:Binding Sites; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C114487:PDCD4 protein, human; D020598:Proto-Oncogene Proteins c-myb; D016601:RNA-Binding Proteins; D007073:Immunoglobulin E
keywords: MYB; PDCD4; asthma; childhood; severe