Genetic variation of αENaC influences lung diffusion during exercise in humans

Exercise, decompensated heart failure, and exposure to high altitude have been shown to cause symptoms of pulmonary edema in some, but not all, subjects, suggesting a genetic component to this response. Epithelial Na(+) Channels (ENaC) regulate Na(+) and fluid reabsorption in the alveolar airspace in the lung. An increase in number and/or activity of ENaC has been shown to increase lung fluid clearance. Previous work has demonstrated common functional genetic variants of the α-subunit of ENaC, including an A→T substitution at amino acid 663 (αA663T). We sought to determine the influence of the T663 variant of αENaC on lung diffusion at rest and at peak exercise in healthy humans. Thirty healthy subjects were recruited for study and grouped according to their SCNN1A genotype [n=17 vs. 13, age=25±7 years vs. 30±10 years, BMI=23±4 kg/m(2) vs. 25±4 kg/m(2), V(O2 peak) = 95±30%pred. vs. 100±31%pred., mean±SD, for AA (homozygous for αA663) vs. AT/TT groups (at least one αT663), respectively]. Measures of the diffusing capacity of the lungs for carbon monoxide (DL(CO)), the diffusing capacity of the lungs for nitric oxide (DL(NO)), alveolar volume (V(A)), and alveolar-capillary membrane conductance (D(M)) were taken at rest and at peak exercise. Subjects expressing the AA polymorphism of ENaC showed a significantly greater percent increase in DL(CO) and DL(NO), and a significantly greater decrease in systemic vascular resistance from rest to peak exercise than those with the AT/TT variant (DL(CO)=51±12% vs. 36±17%, DL(NO)=51±24% vs. 32±25%, SVR=-67±3 vs. -50±8%, p<0.05). The AA ENaC group also tended to have a greater percent increase in DL(CO)/VA from rest to peak exercise, although this did not reach statistical significance (49±26% vs. 33±26%, p=0.08). These results demonstrate that genetic variation of the α-subunit of ENaC at amino acid 663 influences lung diffusion at peak exercise in healthy humans, suggesting differences in alveolar Na(+) and, therefore, fluid handling. These findings could be important in determining who may be susceptible to pulmonary edema in response to various clinical or environmental conditions.