Molecular Genetics and Genomics Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Hum Mutat. 2013 Aug;34(8):1131-9. doi: 10.1002/humu.22340. Epub 2013 May 20.
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.
先前的一项哮喘全基因组关联研究揭示了一些值得进一步研究的潜在关联。在这项研究中，在独立的重症哮喘患者群体中，对在 5%假发现率下具有全基因组显著关联的 SNP 进行了研究。该研究小组由 397 名成年重症哮喘患者、116 名儿童重症哮喘患者和一个由哮喘先证者组成的 207 个家族三体型收集组成。PDCD4 基因中的三个 SNP(rs6585018:G>A、rs1322997:C>A 和 rs34104444:G>A)与严重儿童哮喘(P 值:0.003、0.002、0.004)和总免疫球蛋白 E(IgE)水平(P 值:0.034、0.041、0.052)显著相关。在一个由 234 名哮喘儿童和 652 名对照组成的独立群体中，PDCD4 SNP rs1407696:T>G 和 rs11195360:T>C 与总 IgE 水平相关(P 值:0.006、0.014)。PDCD4 基因座的计算机分析显示，rs6585018:G>A 具有影响 MYB 转录因子结合的潜力，已知其作为 PDCD4 转录诱导剂。电泳迁移率变动分析和报告基因分析显示，rs6585018:G>A 改变了 MYB 结合，从而影响了 PDCD4 的表达。MYB 自身的 SNP 赋予了嗜酸性粒细胞增多和哮喘的易感性。因此，我们在 PDCD4 中的一个变异的 MYB 结合位点与儿童哮喘最严重形式之间的关联表明，PDCD4 是哮喘炎症反应的一个重要的新分子。
