A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis - 06/11/18
Abstract |
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 |
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 (odds ratio, 0.92; P = 1.01 × 10−6) and EVE (odds ratio, 0.85; joint PEVE = 1.31 × 10−13). 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-terminal fragment, potent pyroptotic cell death is induced. The splice 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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Asthma, gasdermin B, GSDMB, 17q21 locus, genetics, airway epithelium, pyroptosis
Abbreviations used : ALI, FACS, GERA, GSDMA, GSDMB, GWAS, HBE, LD, LDH, MAF, NHBE, OR, PAR, QC, SNP
Plan
| This work was supported by National Institutes of Health (NIH) grants (grant nos. R01HL114769 and P30ES000002) and an American Asthma Foundation Scholar award to Q.L. A.D. was supported by grant K01 HL130629-01. B.E.H. was partially supported by the NIH (grant no. R00 HL105663 and R01 HL133433). J.-P. was supported by the American Heart Association (grant no. 13SDG14320004) and by the NIH (grant no. P01HL120839). S.H.R. was supported in part by the NIH (grant no. DK065988). |
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| Disclosure of potential conflict of interest: A. Dahlin's, J. A. Mitchel's, and A. C. Wu's institution received a grant from the National Institutes of Health (NIH) for this work. B. E. Himes's institution received a grant from the NIH for this and other works. S. H. Randell's institution received grant P30DK065988 from the NIH and grant BOUCHE15R0 from the CF Foundation for this work. E. Israel's institution received consultant fees from Novartis, travel expenses from Research in Real Life, and consultancy fees from TEVA specialty Pharmaceuticals; received grants from Genentech, Sanofi, and Boehringer Ingelheim; personally received consultant fees from AstraZeneca, Novartis, Philips Respironics, Regeneron Pharmaceuticals, TEVA Specialty Pharmaceuticals, Bird Rock Bio, Nuvelution Pharmaceuticals, Vitaeris, Inc, Sanofi, Merck, and Entrinsic Health Solutions; and nonfinancial support from Boehringer Ingelheim, GlaxoSmithKline, Merck, Sunovion, and TEVA. K. Tantisira's institution received a grant from the NIH for this and other works. J. Park's institution received grants from the American Heart Association and the NIH for this work. Q. Lu's institution received grant R01HL114769 from the NIH and a grant from the American Asthma Foundation for this work. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 5
P. 1469 - novembre 2018 Retour au numéro
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