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Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways - 04/03/21

Doi : 10.1016/j.jaci.2020.07.030 
Xingnan Li, PhD, MS a, , Stephanie A. Christenson, MD b, Brian Modena, MD c, Huashi Li, MS a, William W. Busse, MD d, Mario Castro, MD e, Loren C. Denlinger, MD, PhD d, Serpil C. Erzurum, MD f, John V. Fahy, MD b, Benjamin Gaston, MD g, Annette T. Hastie, PhD h, Elliot Israel, MD i, Nizar N. Jarjour, MD d, Bruce D. Levy, MD i, Wendy C. Moore, MD h, Prescott G. Woodruff, MD b, Naftali Kaminski, MD j, Sally E. Wenzel, MD k, Eugene R. Bleecker, MD a, Deborah A. Meyers, PhD a
for the

NHLBI Severe Asthma Research Program (SARP)

a Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz 
b Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California at San Francisco, San Francisco, Calif 
c Division of Allergy and Clinical Immunology, Department of Medicine, National Jewish Health, Denver, Colo 
d Department of Medicine, University of Wisconsin School of Medicine & Public Health, Madison, Wis 
e Division of Pulmonary, Critical Care and Sleep Medicine, University of Kansas School of Medicine, Kansas City, Kan 
f Lerner Research Institute and the Respiratory Institute, Cleveland Clinic, Cleveland, Ohio 
g Wells Center for Pediatric Research and Riley Hospital for Children, Indiana University, Indianapolis, Ind 
h Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC 
i Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass 
j Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn 
k Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pa 

Corresponding author: Xingnan Li, PhD, MS, Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, 1230 N Cherry Ave, PO Box 210242, Tucson, AZ 85719.Division of GeneticsGenomics and Precision MedicineDepartment of MedicineUniversity of Arizona1230 N Cherry AvePO Box 210242TucsonAZ85719

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.

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Key words : Antiviral pathways, asthma exacerbations, asthma severity, eQTL, genetics, GSDMA, GSDMB, PGAP3, whole-genome sequence, RNAseq

Abbreviations used : AD, BEC, eQTL, GSDMA, GSDMB, GWAS, IRF, LD, MAF, ORMDL3, PGAP3, QC, RNAseq, SARP, SNP, TOPMed, T1D, WGS


Mappa


 The Severe Asthma Research Program (SARP) cross-sectional cohort was supported by the National Institutes of Health (NIH; grant nos. HL69116, HL69130, HL69149, HL69155, HL69167, HL69170, HL69174, HL69349, UL1RR024992, M01RR018390, M01RR07122, M01RR03186, HL087665, and HL091762). The SARP longitudinal cohort was funded by the National Heart, Lung, and Blood Institute (NHLBI; grant nos. U10 HL109172, HL109168, HL109152, HL109257, HL109146, HL109250, HL109164, and HL109086). Genetic studies for the SARP cross-sectional cohort were funded by the NIH (grant no. HL87665) and Go Grant (grant no. RC2HL101487). SARP whole-genome sequencing was supported by NHLBI Trans-Omics for Precision Medicine X01 grant.
 Disclosure of potential conflict of interest: B. Modena reports grants from the National Heart, Lung, and Blood Institute (NHLBI) and personal fees from Sanofi, Regeneron, GlaxoSmithKline (GSK), Circassia, and AstraZeneca. W. W. Busse has received consulting fees from AstraZeneca, Genentech, Regeneron, Novartis, Sanofi, and GSK. M. Castro receives university grant funding from the National Institutes of Health (NIH), the American Lung Association, and Patient-Centered Outcomes Research Institute, receives pharmaceutical grant funding from AstraZeneca, Chiesi, Novartis, GSK, and Sanofi-Aventis, serves as a consultant for Genentech, Theravance, VIDA, Teva, and Sanofi-Aventis and also as a speaker for AstraZeneca, Genentech, GSK, Regeneron, Sanofi, and Teva, and receives royalties from Elsevier. L. C. Denlinger has active grant funding from the NHLBI and has consulted in the last 3 years with AstraZeneca. A. T. Hastie reports grants from the NIH and grant support from Genentech during the conduct of the study. B. D. Levy reports grants from the NHLBI and personal fees from AstraZeneca, Bayer, Gossamer Bio, Merck, Nocion Therapeutics, Pieris Pharmaceuticals, Teva Pharmaceuticals, SRA, and Sanofi. P. G. Woodruff reports personal fees from Sanofi, Glenmark Pharmaceuticals, Theravance, GSK, NGM Pharma, Amgen, and Genentech. S. E. Wenzel has consulted for AstraZeneca, Genentech, GSK, and Sanofi-Aventis in the last 3 years, in matters unrelated to the content of this manuscript, participated in multicenter clinical trial for AstraZeneca, GSK, Novartis, and Sanofi-Aventis in the last 3 years, unrelated to this manuscript, and received financial support for the last 2 years of SARP from an unrestricted grant from Boehringer Ingelheim. E. R. Bleecker has performed clinical trials through his employer, Wake Forest School of Medicine and University of Arizona, for AstraZeneca, MedImmune, Boehringer Ingelheim, Genentech, Novartis, Regeneron, and Sanofi Genzyme, and has also served as a paid consultant for ALK-Abelló, AstraZeneca, MedImmune, GSK, Novartis, Regeneron, Sanofi Genzyme, and Teva, outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest.


© 2020  American Academy of Allergy, Asthma & Immunology. Pubblicato da Elsevier Masson SAS. Tutti i diritti riservati.
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