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A polymorphism affecting MYB binding within the promoter of the PDCD4 gene is associated with severe asthma in children.

Binia A, Van Stiphout N, Liang L, Michel S, Bhavsar PK, Fan Chung K, Brightling CE, Barnes PJ, Kabesch M, Bush A, Cookson WO, Moffatt MF - Hum. Mutat. (2013)

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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Genetics and Genomics Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom. aristea.binia@rdls.nestle.com

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The PDCD4 gene structure. Haplotype analysis results from the HapMap CEU genotype data (combined Phase I and II) are shown in a color scale map plot expressing the r2 value for linkage disequilibrium (white: r2 = 0, black: r2 = 1). Underlined SNPs were included in the original GWAS study [Moffatt et al., 2007]. SNPs selected in the present study are shown in a frame box. The promoter area 112,621,625 to 112,622,604; NCBI 36.1 (chr10:112,631,200 to 112,632,179; NCBI 37.3) sequenced in the fine mapping study is indicated by the patterned box. The area was entered in the Ensembl Genome Browser (http://www.ensembl.org/index.html) to identify putative regulatory elements in different cell lines (red/green lines: predicted promoter transcription; purple lines: polymerase III-associated region; grey lines and black boxes: unidentified regulatory elements).
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fig02: The PDCD4 gene structure. Haplotype analysis results from the HapMap CEU genotype data (combined Phase I and II) are shown in a color scale map plot expressing the r2 value for linkage disequilibrium (white: r2 = 0, black: r2 = 1). Underlined SNPs were included in the original GWAS study [Moffatt et al., 2007]. SNPs selected in the present study are shown in a frame box. The promoter area 112,621,625 to 112,622,604; NCBI 36.1 (chr10:112,631,200 to 112,632,179; NCBI 37.3) sequenced in the fine mapping study is indicated by the patterned box. The area was entered in the Ensembl Genome Browser (http://www.ensembl.org/index.html) to identify putative regulatory elements in different cell lines (red/green lines: predicted promoter transcription; purple lines: polymerase III-associated region; grey lines and black boxes: unidentified regulatory elements).

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/).


A polymorphism affecting MYB binding within the promoter of the PDCD4 gene is associated with severe asthma in children.

Binia A, Van Stiphout N, Liang L, Michel S, Bhavsar PK, Fan Chung K, Brightling CE, Barnes PJ, Kabesch M, Bush A, Cookson WO, Moffatt MF - Hum. Mutat. (2013)

The PDCD4 gene structure. Haplotype analysis results from the HapMap CEU genotype data (combined Phase I and II) are shown in a color scale map plot expressing the r2 value for linkage disequilibrium (white: r2 = 0, black: r2 = 1). Underlined SNPs were included in the original GWAS study [Moffatt et al., 2007]. SNPs selected in the present study are shown in a frame box. The promoter area 112,621,625 to 112,622,604; NCBI 36.1 (chr10:112,631,200 to 112,632,179; NCBI 37.3) sequenced in the fine mapping study is indicated by the patterned box. The area was entered in the Ensembl Genome Browser (http://www.ensembl.org/index.html) to identify putative regulatory elements in different cell lines (red/green lines: predicted promoter transcription; purple lines: polymerase III-associated region; grey lines and black boxes: unidentified regulatory elements).
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Related In: Results  -  Collection

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fig02: The PDCD4 gene structure. Haplotype analysis results from the HapMap CEU genotype data (combined Phase I and II) are shown in a color scale map plot expressing the r2 value for linkage disequilibrium (white: r2 = 0, black: r2 = 1). Underlined SNPs were included in the original GWAS study [Moffatt et al., 2007]. SNPs selected in the present study are shown in a frame box. The promoter area 112,621,625 to 112,622,604; NCBI 36.1 (chr10:112,631,200 to 112,632,179; NCBI 37.3) sequenced in the fine mapping study is indicated by the patterned box. The area was entered in the Ensembl Genome Browser (http://www.ensembl.org/index.html) to identify putative regulatory elements in different cell lines (red/green lines: predicted promoter transcription; purple lines: polymerase III-associated region; grey lines and black boxes: unidentified regulatory elements).
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/).

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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Genetics and Genomics Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom. aristea.binia@rdls.nestle.com

Show MeSH
Related in: MedlinePlus