Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways

被引：68

作者：

Li, Xingnan ^{[1
]}

Christenson, Stephanie A. ^{[2
]}

Modena, Brian ^{[3
]}

Li, Huashi ^{[1
]}

Busse, William W. ^{[4
]}

Castro, Mario ^{[5
]}

Denlinger, Loren C. ^{[4
]}

Erzurum, Serpil C. ^{[6
,7
]}

Fahy, John V. ^{[2
]}

Gaston, Benjamin ^{[8
,9
]}

Hastie, Annette T. ^{[10
]}

Israel, Elliot ^{[11
,12
]}

Jarjour, Nizar N. ^{[4
]}

Levy, Bruce D. ^{[11
,12
]}

Moore, Wendy C. ^{[10
]}

Woodruff, Prescott G. ^{[2
]}

Kaminski, Naftali ^{[13
]}

Wenzel, Sally E. ^{[14
]}

Bleecker, Eugene R. ^{[1
]}

Meyers, Deborah A. ^{[1
]}

机构：

[1] Univ Arizona, Dept Med, Div Genet Genom & Precis Med, 1230 N Cherry Ave,POB 210242, Tucson, AZ 85719 USA

[2] Univ Calif San Francisco, Dept Med, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA

[3] Natl Jewish Hlth, Dept Med, Div Allergy & Clin Immunol, Denver, CO USA

[4] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Madison, WI 53706 USA

[5] Univ Kansas, Sch Med, Div Pulm Crit Care & Sleep Med, Kansas City, KS USA

[6] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA

[7] Cleveland Clin, Resp Inst, Cleveland, OH 44106 USA

[8] Indiana Univ, Wells Ctr Pediat Res, Indianapolis, IN 46204 USA

[9] Indiana Univ, Riley Hosp Children, Indianapolis, IN 46204 USA

[10] Wake Forest Sch Med, Dept Med, Winston Salem, NC 27101 USA

[11] Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA

[12] Harvard Med Sch, Boston, MA 02115 USA

[13] Yale Sch Med, Div Pulm Crit Care & Sleep Med, Dept Internal Med, New Haven, CT USA

[14] Univ Pittsburgh, Dept Environm & Occupat Hlth, Pittsburgh, PA USA

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2021年 / 147卷 / 03期

关键词：

Antiviral pathways; asthma exacerbations; asthma severity; eQTL; genetics; GSDMA; GSDMB; PGAP3; whole-genome sequence; RNAseq;

D O I：

10.1016/j.jaci.2020.07.030

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

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 x 10(-9) < P < 1.8 x 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.

引用

页码：894 / 909

页数：16

共 92 条

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Eriksson, Nicholas ;

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Abramson, Michael J. ;

Holt, Patrick G. ;

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共 92 条

[21] Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations [J].

Denlinger, Loren C. ;

Phillips, Brenda R. ;

Ramratnam, Sinna ;

Ross, Kristie ;

Bhakta, Nirav R. ;

Cardet, Juan Carlos ;

Castro, Mario ;

Peters, Stephen P. ;

Phipatanakul, Wanda ;

Aujle, Shean ;

Bacharier, Leonard B. ;

Bleecker, Eugene R. ;

Comhair, Suzy A. A. ;

Coverstone, Andrea ;

DeBoer, Mark ;

Erzurum, Serpil C. ;

Fain, Sean B. ;

Fajt, Merritt ;

Fitzpatrick, Anne M. ;

Gaffin, Jonathan ;

Gaston, Benjamin ;

Hastie, Annette T. ;

Hawkins, Gregory A. ;

Holguin, Fernando ;

Irani, Anne-Marie ;

Israel, Elliot ;

Levy, Bruce D. ;

Ngoc Ly ;

Meyers, Deborah A. ;

Moore, Wendy C. ;

Myers, Ross ;

Opina, Maria Theresa D. ;

Peters, Michael C. ;

Schiebler, Mark L. ;

Sorkness, Ronald L. ;

Teague, W. Gerald ;

Wenzel, Sally E. ;

Woodruff, Prescott G. ;

Mauger, David T. ;

Fahy, John V. ;

Jarjour, Nizar N. .

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Epstein, Charles B. ;

Frietze, Seth ;

Harrow, Jennifer ;

Kaul, Rajinder ;

Khatun, Jainab ;

Lajoie, Bryan R. ;

Landt, Stephen G. ;

Lee, Bum-Kyu ;

Pauli, Florencia ;

Rosenbloom, Kate R. ;

Sabo, Peter ;

Safi, Alexias ;

Sanyal, Amartya ;

Shoresh, Noam ;

Simon, Jeremy M. ;

Song, Lingyun ;

Trinklein, Nathan D. ;

Altshuler, Robert C. ;

Birney, Ewan ;

Brown, James B. ;

Cheng, Chao ;

Djebali, Sarah ;

Dong, Xianjun ;

Dunham, Ian ;

Ernst, Jason ;

Furey, Terrence S. ;

Gerstein, Mark ;

Giardine, Belinda ;

Greven, Melissa ;

Hardison, Ross C. ;

Harris, Robert S. ;

Herrero, Javier ;

Hoffman, Michael M. ;

Iyer, Sowmya ;

Kellis, Manolis ;

Khatun, Jainab ;

Kheradpour, Pouya ;

Kundaje, Anshul ;

Lassmann, Timo ;

Li, Qunhua ;

Lin, Xinying ;

Marinov, Georgi K. ;

Merkel, Angelika ;

Mortazavi, Ali .

NATURE, 2012, 489 (7414) :57-74

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Ellinghaus, David ;

Jostins, Luke ;

Spain, Sarah L. ;

Cortes, Adrian ;

Bethune, Joern ;

Han, Buhm ;

Park, Yu Rang ;

Raychaudhuri, Soumya ;

Pouget, Jennie G. ;

Huebenthal, Matthias ;

Folseraas, Trine ;

Wang, Yunpeng ;

Esko, Tonu ;

Metspalu, Andres ;

Westra, Harm-Jan ;

Franke, Lude ;

Pers, Tune H. ;

Weersma, Rinse K. ;

Collij, Valerie ;

D'Amato, Mauro ;

Halfvarson, Jonas ;

Jensen, Anders Boeck ;

Lieb, Wolfgang ;

Degenhardt, Franziska ;

Forstner, Andreas J. ;

Hofmann, Andrea ;

Schreiber, Stefan ;

Mrowietz, Ulrich ;

Juran, Brian D. ;

Lazaridis, Konstantinos N. ;

Brunak, Soren ;

Dale, Anders M. ;

Trembath, Richard C. ;

Weidinger, Stephan ;

Weichenthal, Michael ;

Ellinghaus, Eva ;

Elder, James T. ;

Barker, Jonathan N. W. N. ;

Andreassen, Ole A. ;

McGovern, Dermot P. ;

Karlsen, Tom H. ;

Barrett, Jeffrey C. ;

Parkes, Miles ;

Brown, Matthew A. ;

Franke, Andre .

NATURE GENETICS, 2016, 48 (05) :510-+

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Eyre, Steve ;

Bowes, John ;

Diogo, Dorothee ;

Lee, Annette ;

Barton, Anne ;

Martin, Paul ;

Zhernakova, Alexandra ;

Stahl, Eli ;

Viatte, Sebastien ;

McAllister, Kate ;

Amos, Christopher I. ;

Padyukov, Leonid ;

Toes, Rene E. M. ;

Huizinga, Tom W. J. ;

Wijmenga, Cisca ;

Trynka, Gosia ;

Franke, Lude ;

Westra, Harm-Jan ;

Alfredsson, Lars ;

Hu, Xinli ;

Sandor, Cynthia ;

de Bakker, Paul I. W. ;

Davila, Sonia ;

Khor, Chiea Chuen ;

Heng, Khai Koon ;

Andrews, Robert ;

Edkins, Sarah ;

Hunt, Sarah E. ;

Langford, Cordelia ;

Symmons, Deborah ;

Concannon, Pat ;

Onengut-Gumuscu, Suna ;

Rich, Stephen S. ;

Deloukas, Panos ;

Gonzalez-Gay, Miguel A. ;

Rodriguez-Rodriguez, Luis ;

Arlsetig, Lisbeth ;

Martin, Javier ;

Rantapaa-Dahlqvist, Solbritt ;

Plenge, Robert M. ;

Raychaudhuri, Soumya ;

Klareskog, Lars ;

Gregersen, Peter K. ;

Worthington, Jane .

NATURE GENETICS, 2012, 44 (12) :1336-1340

[26] The Reactome Pathway Knowledgebase [J].

Fabregat, Antonio ;

Jupe, Steven ;

Matthews, Lisa ;

Sidiropoulos, Konstantinos ;

Gillespie, Marc ;

Garapati, Phani ;

Haw, Robin ;

Jassal, Bijay ;

Korninger, Florian ;

May, Bruce ;

Milacic, Marija ;

Roca, Corina Duenas ;

Rothfels, Karen ;

Sevilla, Cristoffer ;

Shamovsky, Veronica ;

Shorser, Solomon ;

Varusai, Thawfeek ;

Viteri, Guilherme ;

Weiser, Joel ;

Wu, Guanming ;

Stein, Lincoln ;

Hermjakob, Henning ;

D'Eustachio, Peter .

NUCLEIC ACIDS RESEARCH, 2018, 46 (D1) :D649-D655

[27] Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology [J].

Ferreira, Manuel A. ;

Vonk, Judith M. ;

Baurecht, Hansjorg ;

Marenholz, Ingo ;

Tian, Chao ;

Hoffman, Joshua D. ;

Helmer, Quinta ;

Tillander, Annika ;

Ullemar, Vilhelmina ;

van Dongen, Jenny ;

Lu, Yi ;

Rueschendorf, Franz ;

Esparza-Gordillo, Jorge ;

Medway, Chris W. ;

Mountjoy, Edward ;

Burrows, Kimberley ;

Hummel, Oliver ;

Grosche, Sarah ;

Brumpton, Ben M. ;

Witte, John S. ;

Hottenga, Jouke-Jan ;

Willemsen, Gonneke ;

Zheng, Jie ;

Rodriguez, Elke ;

Hotze, Melanie ;

Franke, Andre ;

Revez, Joana A. ;

Beesley, Jonathan ;

Matheson, Melanie C. ;

Dharmage, Shyamali C. ;

Bain, Lisa M. ;

Fritsche, Lars G. ;

Gabrielsen, Maiken E. ;

Balliu, Brunilda ;

Nielsen, Jonas B. ;

Zhou, Wei ;

Hveem, Kristian ;

Langhammer, Arnulf ;

Holmen, Oddgeir L. ;

Loset, Mari ;

Abecasis, Goncalo R. ;

Willer, Cristen J. ;

Arnold, Andreas ;

Homuth, Georg ;

Schmidt, Carsten O. ;

Thompson, Philip J. ;

Martin, Nicholas G. ;

Duffy, David L. ;

Novak, Natalija ;

Schulz, Holger .

NATURE GENETICS, 2017, 49 (12) :1752-+

[28] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct [J].

Ferreira, Manuel A. R. ;

Mathur, Riddhima ;

Vonk, Judith M. ;

Szwajda, Agnieszka ;

Brumpton, Ben ;

Granell, Raquel ;

Brew, Bronwyn K. ;

Ullemar, Vilhelmina ;

Lu, Yi ;

Jiang, Yunxuan ;

Magnusson, Patrik K. E. ;

Karlsson, Robert ;

Hinds, David A. ;

Paternoster, Lavinia ;

Koppelman, Gerard H. ;

Almqvist, Catarina .

AMERICAN JOURNAL OF HUMAN GENETICS, 2019, 104 (04) :665-684

[29] Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype [J].

Ferreira, Manuel A. R. ;

Matheson, Melanie C. ;

Tang, Clara S. ;

Granell, Raquel ;

Ang, Wei ;

Hui, Jennie ;

Kiefer, Amy K. ;

Duffy, David L. ;

Baltic, Svetlana ;

Danoy, Patrick ;

Bui, Minh ;

Price, Loren ;

Sly, Peter D. ;

Eriksson, Nicholas ;

Madden, Pamela A. ;

Abramson, Michael J. ;

Holt, Patrick G. ;

Heath, Andrew C. ;

Hunter, Michael ;

Musk, Bill ;

Robertson, Colin F. ;

Le Souef, Peter ;

Montgomery, Grant W. ;

Henderson, A. John ;

Tung, Joyce Y. ;

Dharmage, Shyamali C. ;

Brown, Matthew A. ;

James, Alan ;

Thompson, Philip J. ;

Pennell, Craig ;

Martin, Nicholas G. ;

Evans, David M. ;

Hinds, David A. ;

Hopper, John L. .

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2014, 133 (06) :1564-1571

[30] Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia [J].

Ferreira, Manuel A. R. ;

McRae, Allan F. ;

Medland, Sarah E. ;

Nyholt, Dale R. ;

Gordon, Scott D. ;

Wright, Margaret J. ;

Henders, Anjali K. ;

Madden, Pamela A. ;

Visscher, Peter M. ;

Wray, Naomi R. ;

Heath, Andrew C. ;

Montgomery, Grant W. ;

Duffy, David L. ;

Martin, Nicholas G. .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2011, 19 (04) :458-464

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