A polymorphism affecting MYB binding within the promoter of the PDCD4 gene is associated with severe asthma in children.
Bottom Line: 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.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.
Affiliation: Molecular Genetics and Genomics Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom. email@example.comShow MeSH
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Mentions: The area including the SNPs on PDCD4 (NM_145341.3) genotyped in the original GWAS [Moffatt et al., 2007] was examined and tagging SNPs covering variations not included in the arrays used in the original GWAS were selected using the pair-wise tagging algorithm in Haploview 3.3 (r2 > 0.8) [Barrett et al., 2005]. Linkage disequilibrium (LD) of the area was assessed using the HapMap CEU genotype data (version 2, Phase 1 and 2, http://hapmap.ncbi.nlm.nih.gov/). Genome browsers http://www.ensembl.org/index.html and http://genome.ucsc.edu/ were also used to visualize the LD and the regulatory elements as reported from the Encyclopedia of DNA Elements (ENCODE) project spanning the gene region [Kuhn et al., 2012]. Three additional tagging SNPs and one coding SNP in the PDCD4 (MIM #608610) area (rs1322997:C>A, rs11195360:T>C, rs1407696:T>G, and rs34104444:G>A) were selected to be genotyped in the fine mapping study (Fig. 2). In addition, the putative promoter of PDCD4 was sequenced for the identification of potentially novel polymorphisms in 24 samples with known rs6585018:G>A genotypes (14 AA and 10 GA). Two sets of primers were designed (Invitrogen; http://www.invitrogen.com, sequences available upon request) to amplify 2 promoter regions, 112,621,625 to 112,622,006 and 112,622,164 to 112,622,604 (NCBI Build 36.1). The sequencing results were assembled aligned and visualized using the CodonCode Aligner software Version 2.06 (http://www.codoncode.com/).
Affiliation: Molecular Genetics and Genomics Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom. firstname.lastname@example.org