Genetic variation of SCNN1A influences lung diffusing capacity in cystic fibrosis.

Introduction: Epithelial Na channels (ENaCs) play a crucial role in ion and fluid regulation in the lung. In cystic fibrosis (CF), Na hyperabsorption results from ENaC overactivity, leading to airway dehydration. Previous work has demonstrated functional genetic variation of SCNN1A (the gene encoding the ENaC α-subunit), manifesting as an alanine (A) to threonine (T) substitution at amino acid 663, with the αT663 variant resulting in a more active channel.

Methods: We assessed the influence of genetic variation of SCNN1A on the diffusing capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO), together with alveolar-capillary membrane conductance (DM), pulmonary capillary blood volume, and alveolar volume (VA) at rest and during peak exercise in 18 patients with CF (10 homozygous for αA663 (AA group) and 8 with at least one T663 allele (AT/TT group)). Because of the more active channel, we hypothesized that the AT/TT group would show a greater increase in DLCO, DLNO, and DM with exercise because of exercise-mediated ENaC inhibition and subsequent attenuation of Na hyperabsorption.

Results: The AT/TT group had significantly lower pulmonary function, weight, and body mass index than the AA group. Both groups had similar peak workloads, relative peak oxygen consumptions, and cardiopulmonary responses to exercise. The AT/TT group demonstrated a greater increase in DLNO, DLNO/VA, and DM in response to exercise (% increases: DLNO = 18 ± 11 vs 41 ± 38; DLNO/VA = 14 ± 21 vs 40 ± 37; DM = 15 ± 11 vs 41 ± 38, AA vs AT/TT, respectively). There were no differences between groups in absolute diffusing capacity measures at peak exercise.

Conclusion: These results suggest that genetic variation of the α-subunit of ENaC differentially affects the diffusing capacity response to exercise in patients with CF.