Gene-expression profiles in human nasal polyp tissues and identification of genetic susceptibility in aspirin-intolerant asthma
Gene-expression profiles in human nasal polyp tissues and identification of genetic susceptibility in aspirin-intolerant asthma
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DOI：
10.1111/j.1365-2222.2009.03229.x
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发表时间：
2009-07-01
影响因子：
6.1
通讯作者：
Inoue, I.
中科院分区：
文献类型：
--
作者：
Sekigawa, T.;Tajima, A.;Inoue, I.
阿司匹林不耐受哮喘（AIA）是一种由非甾体抗炎药引起的哮喘亚型，其特征是下气道（哮喘）和上呼吸道（鼻炎和鼻息肉）的侵袭性粘膜炎症。AIA的下气道病变和鼻息肉被认为具有涉及阿司匹林敏感性的共同致病特征，这将反映在AIA息肉的基因表达谱中。本研究旨在通过鼻息肉基因表达分析阐明AIA的发病机制，并通过病例对照关联研究确定AIA的遗传易感性。使用微阵列技术检测了9例AIA患者鼻息肉的整体基因表达，并与5例嗜酸性鼻窦炎（ES）患者鼻息肉进行了比较，ES是一种缺乏阿司匹林敏感性的相关疾病。根据鼻息肉AIA特异性基因表达谱，采用病例对照设计筛选AIA易感性候选基因，并对219例AIA患者、374例非哮喘对照组（CTR）和282例阿司匹林耐受性哮喘（ATA）患者进行筛选。通过基因本体分析，鉴定出免疫应答富集的aia特异性基因143个升高基因和3个降低基因。此外，采用基于k均值的算法对基因进行聚类，鉴定出AIA的一个亚类特征，该亚类特征由18个同样在免疫应答中富集的基因组成。通过检测AIA候选基因中与AIA免疫应答相关的单核苷酸多态性（snp）的等位基因关联，发现两个snp （INDO和IL1R2各一个）与AIA存在显著关联（在AIA与CTR中，经Bonferroni校正后P分别=0.011和0.026）。在AIA- ata关联分析中，观察到两个snp与AIA的适度关联。这些结果表明，从AIA鼻息肉基因表达分析中鉴定出的INDO和IL1R2是AIA的易感基因。
Aspirin-intolerant asthma (AIA) is a subtype of asthma induced by non-steroidal anti-inflammatory drugs and characterized by an aggressive mucosal inflammation of the lower airway (asthma) and the upper airways (rhinitis and nasal polyp). The lower airway lesion and the nasal polyp in AIA are postulated to have common pathogenic features involving aspirin sensitivity that would be reflected in the gene expression profile of AIA polyps.This study was conducted to clarify the pathogenesis of AIA using gene expression analysis in nasal polyps, and identify genetic susceptibilities underlying AIA in a case-control association study.Global gene expression of nasal polyps from nine AIA patients was examined using microarray technology in comparison with nasal polyps from five eosinophilic sinusitis (ES) patients, a related disease lacking aspirin sensitivity. Based on the AIA-specific gene expression profile of nasal polyp, candidate genes for AIA susceptibility were selected and screened by a case-control design of 219 AIA patients, 374 non-asthmatic control (CTR), and 282 aspirin-tolerant asthmatic (ATA) subjects.One hundred and forty-three elevated and three decreased genes were identified as AIA-specific genes that were enriched in immune response according to Gene Ontology analysis. In addition, a k-means-based algorithm was applied to cluster the genes, and a subclass characteristic of AIA comprising 18 genes that were also enriched in immune response was identified. By examining the allelic associations of single nucleotide polymorphisms (SNPs) of AIA candidate genes relevant to an immune response with AIA, two SNPs, one each of INDO and IL1R2, showed significant associations with AIA (P=0.011 and 0.026 after Bonferroni's correction, respectively, in AIA vs. CTR). In AIA-ATA association analysis, modest associations of the two SNPs with AIA were observed.These results indicate that INDO and IL1R2, which were identified from gene expression analyses of nasal polyps in AIA, represent susceptibility genes for AIA.