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

Abstract

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.

• Authors: Xingnan Li, Stephanie A Christenson, Brian Modena, Huashi Li, William W Busse, Mario Castro, Loren C Denlinger, Serpil C Erzurum, John V Fahy, Benjamin Gaston, Annette T Hastie, Elliot Israel, Nizar N Jarjour, Bruce D Levy, Wendy C Moore, Prescott G Woodruff, Naftali Kaminski, Sally E Wenzel, Eugene R Bleecker, Deborah A Meyers, NHLBI Severe Asthma Research Program (SARP)
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 147 Issue 3 Pg. 894-909 (03 2021) ISSN: 1097-6825 [Electronic] United States
• PMID: 32795586 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Chemical References

• GSDMB protein, human
• Neoplasm Proteins

Topics

• Adult
• Asthma (genetics)
• Chromosomes, Human, Pair 17 (genetics)
• Disease Progression
• Genetic Association Studies
• Genotype
• Humans
• Middle Aged
• Neoplasm Proteins (genetics)
• Polymorphism, Single Nucleotide
• Quantitative Trait Loci
• Respiratory Mucosa (physiology)
• Sequence Analysis, RNA
• Severity of Illness Index
• Whole Genome Sequencing