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A7165 - A Splicing Variant in Gasdermin B (GSDMB) Inhibits Epithelial Cell Pyroptosis and Protects Against Asthma
Author Block: R. M. Panganiban1, M. Sun1, A. Dahlin2, H. Park1, M. Kan3, B. E. Himes4, J. Mitchel1, C. Iribarren5, E. Jorgenson5, S. H. Randell6, E. Israel7, K. G. Tantisira2, S. A. Shore1, J. Park1, S. T. Weiss2, W. Ann Chen2, Q. Lu1; 1Molecular and Integrative Physiological Sciences, Harvard TH Chan School of Public Health, Boston, MA, United States, 2Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States, 3Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, United States, 4Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United States, 5Division of Research, Kaiser Permanente Northern California, Oakland, CA, United States, 6Cell Biology and Physiology/Marsico Lung Institute, University of North Carolina, Chapel Hill, Chapel Hill, NC, United States, 7Asthma Research Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
RATIONALE: Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, none of the associated variants has been functionally linked to asthma, and as a result, the identity of the asthma gene(s) remains elusive. METHODS: We used the Exome Aggregation Consortium (ExAC) browser to identify coding (amino acid-changing) variants in the 17q21 locus. Asthma association was analyzed for these variants in both the GERA cohort (16,274 cases and 38,269 matched controls) and the EVE Consortium study. 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 the 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: MAF of rs2305480 is 0.45 for controls and 0.39 for cases; for all EVE cohorts: MAF is 0.32 for controls and 0.27 for cases. GSDMB is highly expressed in differentiated airway epithelial cells, including the ciliated cells. The GSDMB protein is cleaved by inflammatory caspase-1 to release its N-terminal fragment, which induces potent pyroptotic cell death. 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 identifies rs11078928 as a functional splicing variant in GSDMB that reduces asthma risk likely by protecting airway epithelial cells from pyroptotic cell death. Our study demonstrates that the GSDMB splicing variant in normals protects against asthma.