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Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways
- Li, Xingnan;
- Christenson, Stephanie A;
- Modena, Brian;
- Li, Huashi;
- Busse, William W;
- Castro, Mario;
- Denlinger, Loren C;
- Erzurum, Serpil C;
- Fahy, John V;
- Gaston, Benjamin;
- Hastie, Annette T;
- Israel, Elliot;
- Jarjour, Nizar N;
- Levy, Bruce D;
- Moore, Wendy C;
- Woodruff, Prescott G;
- Kaminski, Naftali;
- Wenzel, Sally E;
- Bleecker, Eugene R;
- Meyers, Deborah A;
- Program, NHLBI Severe Asthma Research
Published Web Location
https://doi.org/10.1016/j.jaci.2020.07.030Abstract
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 -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.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.