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CFTR variants are associated with chronic bronchitis in smokers
PDPI Jatim, 07 Jan 2022 23:14:12


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 hypothesize that CFTR variants in individuals with a history of smoking are associated with COPD and related phenotypes.

Methods Whole genome sequencing was performed through the NHLBI TOPMed program in 8597 subjects from the COPDGene 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 2,118 subjects from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) 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-value=0.0025, OR=1.53) and in meta-analysis of COPDGene and ECLIPSE (one sided p-value=0.0060, OR=1.52). Single variant testing revealed that the F508del variant was associated with chronic bronchitis in COPDGene (one sided p-value=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.


This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: CPH has received grants from NHLBI, Alpha-1 Foundation, Bayer, Boehringer-Ingelheim, Novartis and Vertex, and consulting fees from Takeda. AAD has received grants from NHLBI. GRC has received grants from the NIDDK and U.S. CF Foundation. MHC has received grant support from Bayer and GSK, and consulting or speaking fees from Genentech, Astrazeneca, and Illumina. HL has received grants from NHLBI and NIH Office of the Director, and consulting fees as part of the Chan Zuckerberg Rare Disease Consortium. AS, DQ, WK, and KR do not have any conflicts of interest to disclose.

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