TY - JOUR
T1 - CFTR variants are associated with chronic bronchitis in smokers
AU - NHLBI TransOmics in Precision Medicine (TOPMed)
AU - Saferali, Aabida
AU - Qiao, Dandi
AU - Kim, Wonji
AU - Raraigh, Karen
AU - Levy, Hara
AU - Diaz, Alejandro A.
AU - Cutting, Garry R.
AU - Cho, Michael H.
AU - Hersh, Craig P.
N1 - Funding Information:
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.
Funding Information:
Acknowledgements: Molecular data for the Trans-Omics in Precision Medicine (TOPMed) programme was supported by the National Heart, Lung, and Blood Institute (NHLBI). Whole-genome sequencing for “NHLBI TOPMed: Genetic Epidemiology of COPD (COPDGene)” (phs000951) was performed at the Broad Institute Genomics Platform (HHSN268201500014C) and the Northwest Genomics Center (3R01HL08985608S1). Whole-genome sequencing for “NHLBI TOPMed: Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE)” (phs001472) was performed at the McDonnell Genome Institute (HHSN268201600037I). Core support including centralised genomic read mapping and genotype calling, along with variant quality metrics and filtering, was provided by the TOPMed Informatics Research Center (3R01HL11762602S1; contract HHSN268201800002I). Core support including phenotype harmonisation, data management, sample-identity quality control and general programme coordination was provided by the TOPMed Data Coordinating Center (R01HL120393; U01HL120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed.
Funding Information:
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 the Crossref Funder Registry.
Publisher Copyright:
Copyright © The authors 2022.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Introduction Loss-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 that CFTR variants in individuals with a history of smoking are associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. Methods Whole-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 annotated CFTR variants 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. Results We identified 301 coding variants within the CFTR gene 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 more CFTR variants on separate alleles and these subjects were enriched for COPD cases (p=0.010). Conclusions Cigarette smokers who carry one deleterious CFTR variant have higher rates of chronic bronchitis, while presence of two CFTR variants may be associated with COPD. These results indicate that genetically mediated reduction in CFTR function contributes to COPD related phenotypes, in particular chronic bronchitis.
AB - Introduction Loss-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 that CFTR variants in individuals with a history of smoking are associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. Methods Whole-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 annotated CFTR variants 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. Results We identified 301 coding variants within the CFTR gene 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 more CFTR variants on separate alleles and these subjects were enriched for COPD cases (p=0.010). Conclusions Cigarette smokers who carry one deleterious CFTR variant have higher rates of chronic bronchitis, while presence of two CFTR variants may be associated with COPD. These results indicate that genetically mediated reduction in CFTR function contributes to COPD related phenotypes, in particular chronic bronchitis.
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U2 - 10.1183/13993003.01994-2021
DO - 10.1183/13993003.01994-2021
M3 - Article
C2 - 34996830
AN - SCOPUS:85136339288
SN - 0903-1936
VL - 60
JO - European Respiratory Journal, Supplement
JF - European Respiratory Journal, Supplement
IS - 2
M1 - 2101994
ER -