A Polymorphism Affecting MYB Binding within the Promoter of the PDCD4 Gene is Associated with Severe Asthma in Children
Van Stiphout, Nicole
Bhavsar, Pankaj K
Fan Chung, K
Brightling, Chris E
Barnes, Peter J
Cookson, William OC
Moffatt, Miriam FNote: Order does not necessarily reflect citation order of authors.
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CitationBinia, A., N. Van Stiphout, L. Liang, S. Michel, P. K. Bhavsar, K. Fan Chung, C. E. Brightling, et al. 2013. “A Polymorphism Affecting MYB Binding within the Promoter of the PDCD4 Gene is Associated with Severe Asthma in Children.” Human Mutation 34 (8): 1131-1139. doi:10.1002/humu.22340. http://dx.doi.org/10.1002/humu.22340.
AbstractA 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.
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