A functional splicing variant associated with decreased asthma risk abolishes the ability of gasdermin B (GSMDB) to induce epithelial cell pyroptosis.

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BACKGROUND

Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, mechanistic studies have not yet linked any of the associated variants to a function that could influence asthma, and as a result, the identity of the asthma gene(s) remains elusive.

OBJECTIVES

We sought to identify and characterize functional variants in the 17q21 locus.

METHODS

We used the Exome Aggregation Consortium (ExAC) browser to identify coding (amino acid-changing) variants in the 17q21 locus. We obtained asthma association measures for these variants in both the GERA cohort (16,274 cases and 38,269 matched controls) and the EVE Consortium study (5,303 asthma cases and 12,560 individuals). Gene expression and protein localization were determined by quantitative RT-PCR and fluorescence immunostaining, respectively. Molecular and cellular studies were performed to determine the functional effects of coding variants.

RESULTS

Two coding variants (rs2305480 and rs11078928) of the gasdermin B (GSDMB) gene in the 17q21 locus were associated with lower asthma risk in both GERA (OR = 0.92; P= 1.01 × 10-6) and EVE (OR= 0.85; Joint PEVE = 1.31 ×10-13). In GERA, rs11078928 had a minor allele frequency (MAF) of 0.45 in unaffected (non-asthmatic) controls and 0.43 in asthma cases. For European Americans in EVE the MAF of rs2305480 was 0.45 for controls and 0.39 for cases; for all EVE subjects the MAF was 0.32 for controls and 0.27 for cases. GSDMB is highly expressed in differentiated airway epithelial cells, including the ciliated cells. We found that when the GSDMB protein is cleaved by inflammatory caspase-1 to release its N-terminal fragment, potent pyroptotic cell death was induced. The splicing variant rs11078928 deletes the entire exon 6, which encodes 13 amino acids in the critical N-terminus, and abolishes the pyroptotic activity of the GSDMB protein.

CONCLUSIONS

Our study identified a functional asthma variant in the GSDMB gene of the 17q21 locus and implicates GSDMB-mediated epithelial cell pyroptosis in pathogenesis.

Investigators
Abbreviation
J. Allergy Clin. Immunol.
Publication Date
2018-01-09
Pubmed ID
29330013
Medium
Print-Electronic
Full Title
A functional splicing variant associated with decreased asthma risk abolishes the ability of gasdermin B (GSMDB) to induce epithelial cell pyroptosis.
Authors
Panganiban RA, Sun M, Dahlin A, Park HR, Kan M, Himes BE, Mitchel JA, Iribarren C, Jorgenson E, Randell SH, Israel E, Tantisira K, Shore S, Park JA, Weiss ST, Wu AC, Lu Q