Introduction
Chronic obstructive pulmonary disease (COPD) is a complex disease caused by cigarette smoking and influenced by genetic contributors. COPD is phenotypically heterogeneous, with varying manifestations of emphysema, chronic bronchitis, and airway wall thickening and bronchiectasis despite similar degrees of lung function impairment. While mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is associated with cystic fibrosis (CF), data suggests that cigarette smoke results in impaired CFTR function in smokers with and without COPD. Here, we hypothesize that heterozygous mutations in CFTR are associated with COPD and related phenotypes.

Methods:
Whole genome sequencing was performed in 5773 non-Hispanic white subjects, including 3150 moderate COPD (GOLD stage 2-4) cases and 3629 controls, from the COPDGene study through the TOPMed program. Variants within the CFTR gene boundary were annotated using the WGS Annotator pipeline. We examined the occurrence of previously described clinically annotated CFTR variants, and performed single and grouped variant testing for COPD related phenotypes. All association analyses were adjusted for principal components of genetic ancestry, age, gender, pack-years, and current smoking status.

Results
Within the CFTR gene boundary we identified 11,567 polymorphic variants, including 10,577 SNPs and 990 indels. Of these, 10,442 have been previously described. The majority of these variants are located in intergenic (1831) or intronic (7611) regions; 199 are nonsynonymous coding variants. Out of the 400 variants in the CFTR2 database of CF mutations, 75 were polymorphic in our data; of these 29 are known to be CF-causing. We identified 177 individuals who are heterozygous for deltaF508 mutation, and 80 subjects heterozygous for the 28 additional known CF-causing mutations. This combination of 29 CFTR mutations was nominally associated with chronic bronchitis (0.015) but not COPD or emphysema. Furthermore, burden testing weighting with percent pancreatic insufficiency as a measure of mutation severity revealed that the CF causing mutations were additionally associated with bronchodilator response (p=0.018).
Conclusions
We found that a subset of 29 CFTR variants may be associated with chronic bronchitis in non-Hispanic white smokers. This suggests that heterozygous CFTR mutations together with cigarette smoking could result in pulmonary disease through lack of functional CFTR activity.