@article{e229cf9111394626a87ce64182dc7a0b,
title = "Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium",
abstract = "Background: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. Methods: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. Results: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. Conclusions: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.",
keywords = "ACE2, Bronchial epithelium, COVID-19, SARS-CoV-2, eQTL",
author = "{NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS)} and Silva Kasela and Ortega, {Victor E.} and Molly Martorella and Suresh Garudadri and Jenna Nguyen and Elizabeth Ampleford and Anu Pasanen and Srilaxmi Nerella and Buschur, {Kristina L.} and Barjaktarevic, {Igor Z.} and Barr, {R. Graham} and Bleecker, {Eugene R.} and Bowler, {Russell P.} and Comellas, {Alejandro P.} and Cooper, {Christopher B.} and Couper, {David J.} and Criner, {Gerard J.} and Curtis, {Jeffrey L.} and Han, {Mei Lan K.} and Hansel, {Nadia N.} and Hoffman, {Eric A.} and Kaner, {Robert J.} and Krishnan, {Jerry A.} and Martinez, {Fernando J.} and McDonald, {Merry Lynn N.} and Meyers, {Deborah A.} and Robert Paine and Peters, {Stephen P.} and Mario Castro and Denlinger, {Loren C.} and Erzurum, {Serpil C.} and Fahy, {John V.} and Elliot Israel and Jarjour, {Nizar N.} and Levy, {Bruce D.} and Xingnan Li and Moore, {Wendy C.} and Wenzel, {Sally E.} and Joe Zein and Alexis, {Neil E.} and Anderson, {Wayne H.} and Mehrdad Arjomandi and Igor Barjaktarevic and Patricia Basta and Bateman, {Lori A.} and Bhatt, {Surya P.} and Boucher, {Richard C.} and Christenson, {Stephanie A.} and Crystal, {Ronald G.} and Doerschuk, {Claire M.} and Dransfield, {Mark T.} and Brad Drummond and Freeman, {Christine M.} and Craig Galban and Han, {Mei Lan K.} and Hastie, {Annette T.} and Yvonne Huang and Kanner, {Richard E.} and Kleerup, {Eric C.} and LaVange, {Lisa M.} and Lazarus, {Stephen C.} and Newell, {John D.} and Robert Paine and Laura Paulin and Cheryl Pirozzi and Nirupama Putcha and Oelsner, {Elizabeth C.} and O{\textquoteright}Neal, {Wanda K.} and Sanjeev Raman and Rennard, {Stephen I.} and Tashkin, {Donald P.} and Wells, {J. Michael} and Wise, {Robert A.} and Namiko Abe and Gon{\c c}alo Abecasis and Francois Aguet and Christine Albert and Laura Almasy and Alvaro Alonso and Seth Ament and Peter Anderson and Pramod Anugu and Deborah Applebaum-Bowden and Kristin Ardlie and Dan Arking and Arnett, {Donna K.} and Allison Ashley-Koch and Stella Aslibekyan and Tim Assimes and Paul Auer and Dimitrios Avramopoulos and John Barnard and Kathleen Barnes and Emily Barron-Casella and Lucas Barwick and Terri Beaty and Gerald Beck and Diane Becker and Lewis Becker and Rebecca Beer and Amber Beitelshees and Emelia Benjamin and Takis Benos and Marcos Bezerra and Larry Bielak and Joshua Bis and Thomas Blackwell and John Blangero and Eric Boerwinkle and Bowden, {Donald W.} and Russell Bowler and Jennifer Brody and Ulrich Broeckel and Jai Broome and Karen Bunting and Esteban Burchard and Carlos Bustamante and Erin Buth and Brian Cade and Jonathan Cardwell and Vincent Carey and Cara Carty and Richard Casaburi and James Casella and Peter Castaldi and Mark Chaffin and Christy Chang and Chang, {Yi Cheng} and Daniel Chasman and Sameer Chavan and Chen, {Bo Juen} and Chen, {Wei Min} and Chen, {Yii Der Ida} and Michael Cho and Choi, {Seung Hoan} and Chuang, {Lee Ming} and Mina Chung and Chung, {Ren Hua} and Clary Clish and Suzy Comhair and Matthew Conomos and Elaine Cornell and Adolfo Correa and Carolyn Crandall and James Crapo and Cupples, {L. Adrienne} and Joanne Curran and Jeffrey Curtis and Brian Custer and Coleen Damcott and Dawood Darbar and Sayantan Das and Sean David and Colleen Davis and Michelle Daya and {de Andrade}, Mariza and {de las Fuentes}, Lisa and Michael DeBaun and Ranjan Deka and Dawn DeMeo and Scott Devine and Qing Duan and Ravi Duggirala and Durda, {Jon Peter} and Susan Dutcher and Charles Eaton and Lynette Ekunwe and Boueiz, {Adel El} and Patrick Ellinor and Leslie Emery and Serpil Erzurum and Charles Farber and Tasha Fingerlin and Matthew Flickinger and Myriam Fornage and Nora Franceschini and Chris Frazar and Mao Fu and Fullerton, {Stephanie M.} and Lucinda Fulton and Stacey Gabriel and Weiniu Gan and Shanshan Gao and Yan Gao and Margery Gass and Bruce Gelb and Geng, {Xiaoqi (Priscilla)} and Mark Geraci and Soren Germer and Robert Gerszten and Auyon Ghosh and Richard Gibbs and Chris Gignoux and Mark Gladwin and David Glahn and Stephanie Gogarten and Gong, {Da Wei} and Gu, {C. Charles} and Rao, {D. C.} and Sung, {Yun Ju}",
note = "Funding Information: The project officers from the Lung Division of the National Heart, Lung, and Blood Institute were Lisa Postow, PhD, and Lisa Viviano, BSN; SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), grants from the NIH/NHLBI (U01 HL137880 and U24 HL141762), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. Funding Information: The authors thank the SPIROMICS participants and participating physicians, investigators, and staff for making this research possible. More information about the study and how to access SPIROMICS data is available at www.spiromics.org. The authors would like to acknowledge the University of North Carolina at Chapel Hill BioSpecimen Processing Facility for sample processing, storage, and sample disbursements (http://bsp.web.unc.edu/). Funding Information: Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). Genome Sequencing for “NHLBI TOPMed: SubPopulations and InteRmediate Outcome Measures In COPD Study” (phs001927) was performed at the Broad Institute Genomics Platform (HHSN268201600034I). 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 (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. A list of banner authors for the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium is provided in the Additional file . Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1186/s13073-021-00866-2",
language = "English",
volume = "13",
journal = "Genome Medicine",
issn = "1756-994X",
number = "1",
}