Xingnan Li1, Stephanie A Christenson2, Brian Modena3, Huashi Li4, William W Busse5, Mario Castro6, Loren C Denlinger5, Serpil C Erzurum7, John V Fahy2, Benjamin Gaston8, Annette T Hastie9, Elliot Israel10, Nizar N Jarjour5, Bruce D Levy10, Wendy C Moore9, Prescott G Woodruff2, Naftali Kaminski11, Sally E Wenzel12, Eugene R Bleecker4, Deborah A Meyers4. 1. Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz. Electronic address: lixingnan1@deptofmed.arizona.edu. 2. Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California at San Francisco, San Francisco, Calif. 3. Division of Allergy and Clinical Immunology, Department of Medicine, National Jewish Health, Denver, Colo. 4. Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz. 5. Department of Medicine, University of Wisconsin School of Medicine & Public Health, Madison, Wis. 6. Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, Kan. 7. Lerner Research Institute and the Respiratory Institute, Cleveland Clinic, Cleveland, Ohio. 8. Wells Center for Pediatric Research and Riley Hospital for Children, Indiana University, Indianapolis, Ind. 9. Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC. 10. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass. 11. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn. 12. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pa.
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.
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: Nitish Rana; Giuseppe Privitera; Hannah C Kondolf; Katarzyna Bulek; Susana Lechuga; Carlo De Salvo; Daniele Corridoni; Agne Antanaviciute; Rebecca L Maywald; Alexander M Hurtado; Junjie Zhao; Emina H Huang; Xiaoxia Li; E Ricky Chan; Alison Simmons; Giorgos Bamias; Derek W Abbott; Jason D Heaney; Andrei I Ivanov; Theresa T Pizarro Journal: Cell Date: 2022-01-11 Impact factor: 41.582
Authors: Tiantian Du; Jie Gao; Peilong Li; Yunshan Wang; Qiuchen Qi; Xiaoyan Liu; Juan Li; Chuanxin Wang; Lutao Du Journal: Clin Transl Med Date: 2021-08
Authors: Kim Valette; Zhonglin Li; Valentin Bon-Baret; Arnaud Chignon; Jean-Christophe Bérubé; Aida Eslami; Jennifer Lamothe; Nathalie Gaudreault; Philippe Joubert; Ma'en Obeidat; Maarten van den Berge; Wim Timens; Don D Sin; David C Nickle; Ke Hao; Catherine Labbé; Krystelle Godbout; Andréanne Côté; Michel Laviolette; Louis-Philippe Boulet; Patrick Mathieu; Sébastien Thériault; Yohan Bossé Journal: Commun Biol Date: 2021-06-08