BACKGROUND: Cigarette smoking causes Chronic Obstructive Pulmonary Disease 
(COPD), the 3rd leading cause of death in the U.S. CFTR ion transport 
dysfunction has been implicated in COPD pathogenesis, and is associated with 
chronic bronchitis. However, susceptibility to smoke induced lung injury is 
variable and the underlying genetic contributors remain unclear. We hypothesized 
that presence of CFTR mutation heterozygosity may alter susceptibility to 
cigarette smoke induced CFTR dysfunction. Consequently, COPD patients with 
chronic bronchitis may have a higher rate of CFTR mutations compared to the 
general population.
METHODS: Primary human bronchial epithelial cells derived from F508del CFTR 
heterozygotes and mice with (CFTR+/-) and without (CFTR+/+) CFTR heterozygosity 
were exposed to whole cigarette smoke (WCS); CFTR-dependent ion transport was 
assessed by Ussing chamber electrophysiology and nasal potential difference 
measurements, respectively. Caucasians with COPD and chronic bronchitis, age 40 
to 80 with FEV1/FVC < 0.70 and FEV1 < 60% predicted, were selected for genetic 
analysis from participants in the NIH COPD Clinical Research Network's 
Azithromycin for Prevention of Exacerbations of COPD in comparison to 32,900 
Caucasian women who underwent prenatal genetic testing. Genetic analysis 
involved an allele-specific genotyping of 89 CFTR mutations.
RESULTS: Exposure to WCS caused a pronounced reduction in CFTR activity in both 
CFTR (+/+) cells and F508del CFTR (+/-) cells; however, neither the degree of 
decrement (44.7% wild-type vs. 53.5% F508del heterozygous, P = NS) nor the 
residual CFTR activity were altered by CFTR heterozygosity. Similarly, WCS 
caused a marked reduction in CFTR activity measured by NPD in both wild type and 
CFTR heterozygous mice, but the severity of decrement (91.1% wild type vs. 47.7% 
CF heterozygous, P = NS) and the residual activity were not significantly 
affected by CFTR genetic status. Five of 127 (3.9%) COPD patients with chronic 
bronchitis were heterozygous for CFTR mutations which was not significantly 
different from controls (4.5%) (P = NS).
CONCLUSIONS: The magnitude of WCS induced reductions in CFTR activity was not 
affected by the presence of CFTR mutation heterozygosity. CFTR mutations do not 
increase the risk of COPD with chronic bronchitis. CFTR dysfunction due to 
smoking is primarily an acquired phenomenon and is not affected by the presence 
of congenital CFTR mutations.