Abstract
IntroductionLoss-of-function variants in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF); however, there is evidence that reduction in CFTR function due to the presence of one deleterious variant can have clinical consequences. Here, we hypothesise thatCFTR变异个体的吸烟史are associated with chronic obstructive pulmonary disease (COPD) and related phenotypes.
MethodsWhole-genome sequencing was performed through the National Heart, Lung, and Blood Institute TOPMed (TransOmics in Precision Medicine) programme in 8597 subjects from the COPDGene (Genetic Epidemiology of COPD) study, an observational study of current and former smokers. We extracted clinically annotatedCFTRvariants and performed single-variant and variant-set testing for COPD and related phenotypes. Replication was performed in 2118 subjects from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study.
ResultsWe identified 301 coding variants within theCFTRgene boundary: 147 of these have been reported in individuals with CF, including 36 CF-causing variants. We found that CF-causing variants were associated with chronic bronchitis in variant-set testing in COPDGene (one-sided p=0.0025; OR 1.53) and in meta-analysis of COPDGene and ECLIPSE (one-sided p=0.0060; OR 1.52). Single-variant testing revealed that the F508del variant was associated with chronic bronchitis in COPDGene (one-sided p=0.015; OR 1.47). In addition, we identified 32 subjects with two or moreCFTRvariants on separate alleles and these subjects were enriched for COPD cases (p=0.010).
ConclusionsCigarette smokers who carry one deleteriousCFTRvariant have higher rates of chronic bronchitis, while presence of twoCFTRvariants may be associated with COPD. These results indicate that genetically mediated reduction in CFTR function contributes to COPD related phenotypes, in particular chronic bronchitis.
Abstract
Cigarette smokers who carry one deleteriousCFTRvariant have higher rates of chronic bronchitis, while presence of twoCFTRvariants associates with COPD. These results indicate that genetically mediated reduction in CFTR function contributes to COPD.https://bit.ly/3GSWUXw
Footnotes
This article has an editorial commentary:https://doi.org/10.1183/13993003.00898-2022
COPDGene Investigators – Core Units: Administrative Center: James D. Crapo (PI), Edwin K. Silverman (PI), Barry J. Make, Elizabeth A. Regan. Genetic Analysis Center: Terri Beaty, Ferdouse Begum, Peter J. Castaldi, Michael Cho, Dawn L. DeMeo, Adel R. Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan Laird, Christoph Lange, Sharon M. Lutz, Merry-Lynn McDonald, Margaret M. Parker, Dmitry Prokopenko, Dandi Qiao, Elizabeth A. Regan, Phuwanat Sakornsakolpat, Edwin K. Silverman, Emily S. Wan, Sungho Won. Imaging Center: Juan Pablo Centeno, Jean-Paul Charbonnier, Harvey O. Coxson, Craig J. Galban, MeiLan K. Han, Eric A. Hoffman, Stephen Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, Pietro Nardelli, John D. Newell Jr, Aleena Notary, Andrea Oh, Elizabeth A. Regan, James C. Ross, Raul San Jose Estepar, Joyce Schroeder, Jered Sieren, Berend C. Stoel, Juerg Tschirren, Edwin Van Beek, Bram van Ginneken, Eva van Rikxoort, Gonzalo Vegas Sanchez-Ferrero, Lucas Veitel, George R. Washko, Carla G. Wilson. PFT QA Center, Salt Lake City, UT: Robert Jensen. Data Coordinating Center and Biostatistics, National Jewish Health, Denver, CO: Douglas Everett, Jim Crooks, Katherine Pratte, Matt Strand, Carla G. Wilson. Epidemiology Core, University of Colorado Anschutz Medical Campus, Aurora, CO: John E. Hokanson, Gregory Kinney, Sharon M. Lutz, Kendra A. Young. Mortality Adjudication Core: Surya P. Bhatt, Jessica Bon, Alejandro A. Diaz, MeiLan K. Han, Barry Make, Susan Murray, Elizabeth Regan, Xavier Soler, Carla G. Wilson. Biomarker Core: Russell P. Bowler, Katerina Kechris, Farnoush Banaei-Kashani.
COPDGene Investigators – Clinical Centers: Ann Arbor VA: Jeffrey L. Curtis, Perry G. Pernicano. Baylor College of Medicine, Houston, TX: Nicola Hanania, Mustafa Atik, Aladin Boriek, Kalpatha Guntupalli, Elizabeth Guy, Amit Parulekar. Brigham and Women's Hospital, Boston, MA: Dawn L. DeMeo, Alejandro A. Diaz, Lystra P. Hayden, Brian D. Hobbs, Craig Hersh, Francine L. Jacobson, George Washko. Columbia University, New York, NY: R. Graham Barr, John Austin, Belinda D'Souza, Byron Thomashow. Duke University Medical Center, Durham, NC: Neil MacIntyre Jr, H. Page McAdams, Lacey Washington. Grady Memorial Hospital, Atlanta, GA:Eric Flenaugh, Silanth Terpenning. HealthPartners Research Institute, Minneapolis, MN: Charlene McEvoy, Joseph Tashjian. Johns Hopkins University, Baltimore, MD: Robert Wise, Robert Brown, Nadia N. Hansel, Karen Horton, Allison Lambert, Nirupama Putcha. Lundquist Institute for Biomedical Innovation at Harbor UCLA Medical Center, Torrance, CA: Richard Casaburi, Alessandra Adami, Matthew Budoff, Hans Fischer, Janos Porszasz, Harry Rossiter, William Stringer. Michael E. DeBakey VAMC, Houston, TX: Amir Sharafkhaneh, Charlie Lan. Minneapolis VA: Christine Wendt, Brian Bell, Ken M. Kunisaki. National Jewish Health, Denver, CO: Russell Bowler, David A. Lynch. Reliant Medical Group, Worcester, MA: Richard Rosiello, David Pace. Temple University, Philadelphia, PA: Gerard Criner, David Ciccolella, Francis Cordova, Chandra Dass, Gilbert D'Alonzo, Parag Desai, Michael Jacobs, Steven Kelsen, Victor Kim, A. James Mamary, Nathaniel Marchetti, Aditi Satti, Kartik Shenoy, Robert M. Steiner, Alex Swift, Irene Swift, Maria Elena Vega-Sanchez. University of Alabama, Birmingham, AL: Mark Dransfield, William Bailey, Surya P. Bhatt, Anand Iyer, Hrudaya Nath, J. Michael Wells. University of California, San Diego, CA: Douglas Conrad, Xavier Soler, Andrew Yen. University of Iowa, Iowa City, IA: Alejandro P. Comellas, Karin F. Hoth, John Newell Jr, Brad Thompson. University of Michigan, Ann Arbor, MI: MeiLan K. Han, Ella Kazerooni, Wassim Labaki, Craig Galban, Dharshan Vummidi. University of Minnesota, Minneapolis, MN: Joanne Billings, Abbie Begnaud, Tadashi Allen. University of Pittsburgh, Pittsburgh, PA: Frank Sciurba, Jessica Bon, Divay Chandra, Carl Fuhrman, Joel Weissfeld. University of Texas Health, San Antonio, San Antonio, TX: Antonio Anzueto, Sandra Adams, Diego Maselli-Caceres, Mario E. Ruiz, Harjinder Singh.
Conflict of interest: C.P. Hersh has received grants from the NHLBI, Alpha-1 Foundation, Bayer, Boehringer Ingelheim, Novartis and Vertex, and consulting fees from Takeda. A.A. Diaz has received grants from the NHLBI. G.R. Cutting has received grants from the NIDDK and US CF Foundation. M.H. Co has received grant support from Bayer and GSK, and consulting or speaking fees from Genentech, AstraZeneca and Illumina. H. Levy has received grants from the NHLBI and NIH Office of the Director, and consulting fees as part of the Chan Zuckerberg Rare Disease Consortium. A. Saferali, D. Qiao, W. Kim and K. Raraigh do not have any conflicts of interest to disclose.
Support statement: This work was supported by National Institutes of Health grants R01HL133137, R01HL149861, R01DK044003, R01HL130512, R01HL149861, R01HL135142, R01HL137927, R01HL089856, R01HL147148, U01HL089897, U01HL089856, T32HL007427, K01HL157613 and K01HL129039. COPDGene is also supported by the COPD Foundation through contributions made to an industry advisory board comprising AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens and Sunovion. Funding information for this article has been deposited with theCrossref Funder Registry.
- ReceivedAugust 3, 2021.
- AcceptedDecember 14, 2021.
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