[The copyright line for this article was changed on 29 May 2014 after original online publication.]
A Polymorphism Affecting MYB Binding within the Promoter of the PDCD4 Gene is Associated with Severe Asthma in Children
Article first published online: 20 MAY 2013
© 2013 The Authors. *Human Mutation published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 34, Issue 8, pages 1131–1139, August 2013
How to Cite
Binia, A., Van Stiphout, N., Liang, L., Michel, S., Bhavsar, P. K., Fan Chung, K., Brightling, C. E., Barnes, P. J., Kabesch, M., Bush, A., Cookson, W. O.C. and Moffatt, M. F. (2013), A Polymorphism Affecting MYB Binding within the Promoter of the PDCD4 Gene is Associated with Severe Asthma in Children. Hum. Mutat., 34: 1131–1139. doi: 10.1002/humu.22340
Contract grant sponsor: Wellcome Trust (WT077959/Z/05/Z); European Commission as part of GABRIEL (018996).
Communicated by Ian M. N. Day
- Issue published online: 15 JUL 2013
- Article first published online: 20 MAY 2013
- Accepted manuscript online: 18 APR 2013 02:09PM EST
- Manuscript Accepted: 12 APR 2013
- Manuscript Received: 1 NOV 2012
- Wellcome Trust. Grant Number: WT077959/Z/05/Z
- European Commission as part of GABRIEL. Grant Number: 018996
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.