Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways

Abstract Background 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 Whole-genome sequence and RNAseq from human bronchial epithelial cells (BEC) were comprehensively investigated to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program (SARP). Methods eQTL analysis (n=114), correlation analysis (n=156) of gene expression and asthma phenotypes, and pathway analysis were performed in BEC and replicated. Genetic association for asthma severity (426 severe vs. 531 non-severe asthma) and longitudinal asthma exacerbations (n=273) was performed. Results Multiple SNPs in GSDMB associated with asthma severity (odds ratio>1.25) and longitudinal asthma exacerbations (p Conclusions By using a unique set of gene expression data from lung cells obtained using bronchoscopy from comprehensively characterized asthma subjects, 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.