A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis

作者：Ronald Allan M. Panganiban, Maoyun Sun, Amber Dahlin, Hae‐Ryung Park, Mengyuan Kan, Blanca E. Himes, Jennifer A. Mitchel, Carlos Iribarren, Eric Jorgenson, Scott H. Randell, Elliot Israel, Kelan G. Tantisira, Stephanie Shore, Jin‐Ah Park, Scott T. Weiss, Ann Chen Wu, Quan Lu · 发表于：Journal of Allergy and Clinical Immunology · 年份：2018 · DOI：10.1016/j.jaci.2017.11.040 · 被引用次数：208 · 研究领域：Inflammasome and immune disorders、Asthma and respiratory diseases、Spondyloarthritis Studies and Treatments

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 browser to identify coding (amino acid-changing) variants in the 17q21 locus. We obtained asthma association measures for these variants in both the Genetic Epidemiology Research in Adult Health and Aging (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: ). In GERA, rs11078928 had a minor allele frequency (MAF) of 0.45 in unaffected (nonasthmatic) 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-term...