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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 894-909 |
| Number of pages | 16 |
| Journal | Journal of Allergy and Clinical Immunology |
| Volume | 147 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2021 |
Keywords
- Antiviral pathways
- GSDMA
- GSDMB
- PGAP3
- RNAseq
- asthma exacerbations
- asthma severity
- eQTL
- genetics
- whole-genome sequence
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
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Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways. / NHLBI Severe Asthma Research Program (SARP).
In: Journal of Allergy and Clinical Immunology, Vol. 147, No. 3, 03.2021, p. 894-909.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways
AU - NHLBI Severe Asthma Research Program (SARP)
AU - Li, Xingnan
AU - Christenson, Stephanie A.
AU - Modena, Brian
AU - Li, Huashi
AU - Busse, William W.
AU - Castro, Mario
AU - Denlinger, Loren C.
AU - Erzurum, Serpil C.
AU - Fahy, John V.
AU - Gaston, Benjamin
AU - Hastie, Annette T.
AU - Israel, Elliot
AU - Jarjour, Nizar N.
AU - Levy, Bruce D.
AU - Moore, Wendy C.
AU - Woodruff, Prescott G.
AU - Kaminski, Naftali
AU - Wenzel, Sally E.
AU - Bleecker, Eugene R.
AU - Meyers, Deborah A.
N1 - Funding Information: 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. Funding Information: Severe Asthma Research Program (SARP) is a currently active multicenter program funded for the last 18 years by the National Heart, Lung, and Blood Institute. Subjects with mild to severe asthma (enriched for severe) and a subset of controls have been extensively studied using standardized protocols. The earlier SARP cohort was cross-sectional (n = 1644). In a subset of subjects with mild to severe asthma, RNA was isolated from epithelial cells (bronchial epithelial cells [BECs]; n = 155), which were obtained from brush biopsies ( Table I ; see Table E1 in this article’s Online Repository at www.jacionline.org ). 62-64 The current SARP cohort is an ongoing longitudinal study (n = 714). 65-67 Bronchoscopy was performed on a subset of the longitudinal cohort to obtain epithelial cells from brush biopsies (n = 156) for RNA sequence (RNAseq) ( Table I and Table E1 ). All studies were approved by the appropriate institutional review board at the participating sites including informed consent. Funding Information: 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.We acknowledge all investigators, staff, and participants in the SARP studies. TOPMed Acknowledgments: Molecular data for the TOPMed program were supported by the National Heart, Lung, and Blood Institute (NHLBI). Genome sequencing for ?NHLBI TOPMed: Severe Asthma Research Program? (phs001446) was performed at the New York Genome Center (HHSN268201500016C). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (grant no. 3R01HL-117626-02S1; contract no. HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (grant nos. R01HL-120393 and U01HL-120393; contract no. HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. 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-Abell?, 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. Funding Information: 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. Funding Information: TOPMed Acknowledgments: Molecular data for the TOPMed program were supported by the National Heart, Lung, and Blood Institute (NHLBI). Genome sequencing for “NHLBI TOPMed: Severe Asthma Research Program” (phs001446) was performed at the New York Genome Center (HHSN268201500016C). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (grant no. 3R01HL-117626-02S1; contract no. HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (grant nos. R01HL-120393 and U01HL-120393; contract no. HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Publisher Copyright: © 2020 American Academy of Allergy, Asthma & Immunology
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - Antiviral pathways
KW - GSDMA
KW - GSDMB
KW - PGAP3
KW - RNAseq
KW - asthma exacerbations
KW - asthma severity
KW - eQTL
KW - genetics
KW - whole-genome sequence
UR - http://www.scopus.com/inward/record.url?scp=85091255158&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091255158&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2020.07.030
DO - 10.1016/j.jaci.2020.07.030
M3 - Article
C2 - 32795586
AN - SCOPUS:85091255158
VL - 147
SP - 894
EP - 909
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 3
ER -