Background

The Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium.

Objectives

We sought to comprehensively investigate whole-genome sequence and RNA sequence from human bronchial epithelial cells to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program.

Methods

Expression quantitative trait loci analysis (n = 114), correlation analysis (n = 156) of gene expression and asthma phenotypes, and pathway analysis were performed in bronchial epithelial cells and replicated. Genetic association for asthma severity (426 severe vs 531 nonsevere asthma) and longitudinal asthma exacerbations (n = 273) was performed.

Results

Multiple SNPs in gasdermin B (GSDMB) associated with asthma severity (odds ratio, >1.25) and longitudinal asthma exacerbations (P < .05). Expression quantitative trait loci analyses identified multiple SNPs associated with expression levels of post-GPI attachment to proteins 3, GSDMB, or gasdermin A (3.1 × 10⁻⁹ < P < 1.8 × 10⁻⁴). Higher expression levels of GSDMB correlated with asthma and greater number of exacerbations (P < .05). Expression levels of GSDMB correlated with genes involved in IFN signaling, MHC class I antigen presentation, and immune system pathways (false-discovery rate–adjusted P < .05). rs1031458 and rs3902920 in GSDMB colocalized with IFN regulatory factor binding sites and associated with GSDMB expression, asthma severity, and asthma exacerbations (P < .05).

Conclusions

By using a unique set of gene expression data from lung cells obtained using bronchoscopy from comprehensively characterized subjects with asthma, we show that SNPs in GSDMB associated with asthma severity, exacerbations, and GSDMB expression levels. Furthermore, its expression levels correlated with asthma exacerbations and antiviral pathways. Thus, GSDMB is a functional gene for both asthma susceptibility and severity.

中文翻译：

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遗传分析确定了与哮喘严重程度、恶化和抗病毒途径相关的 GSDMB

背景

Chr17q12-21.2 区域是与哮喘易感性最强且最一致的相关区域。由于连锁不平衡，功能基因或单核苷酸多态性（SNP）不明显。

目标

我们试图全面研究来自人支气管上皮细胞的全基因组序列和 RNA 序列，以剖析严重哮喘研究计划中哮喘严重程度的功能基因/SNP。

方法

在支气管上皮细胞中进行表达数量性状基因座分析 (n = 114)、基因表达和哮喘表型的相关性分析 (n = 156) 和通路分析并进行复制。进行了哮喘严重程度（426 例重度对 531 例非重度哮喘）和纵向哮喘加重（n = 273）的遗传关联。

结果

gasdermin B ( GSDMB ) 中的多个 SNP 与哮喘严重程度（优势比，>1.25）和纵向哮喘恶化（P  <.05）相关。表达数量性状基因座分析鉴定了与 GPI 后附着于蛋白质 3、GSDMB或 gasdermin A 的表达水平相关的多个 SNP（3.1 × 10 ^-9  < P  < 1.8 × 10 ^-4）。GSDMB的较高表达水平与哮喘和更多的恶化次数相关（P  < .05）。GSDMB的表达水平与参与 IFN 信号传导、MHC I 类抗原呈递和免疫系统途径的基因相关（错误发现率调整P  < .05)。GSDMB 中的 rs1031458 和 rs3902920与IFN 调节因子结合位点共定位，并与GSDMB表达、哮喘严重程度和哮喘恶化有关 ( P  < .05)。

结论

通过使用从全面表征的哮喘患者的支气管镜检查获得的一组独特的肺细胞基因表达数据，我们表明GSDMB中的 SNP 与哮喘严重程度、恶化和GSDMB表达水平相关。此外，其表达水平与哮喘恶化和抗病毒途径相关。因此，GSDMB是哮喘易感性和严重程度的功能基因。