Genetic variation of the alpha subunit of the epithelial Na+ channel influences exhaled Na+ in healthy humans

Abstract

Epithelial Na+ Channels (ENaC) are located on alveolar cells and are important in β2-adrenergic receptor-mediated lung fluid clearance through the removal of Na+ from the alveolar airspace. Previous work has demonstrated that genetic variation of the alpha subunit of ENaC at amino acid 663 is important in channel function: cells with the genotype resulting in alanine at amino acid 663 (A663) demonstrate attenuated function when compared to genotypes with at least one allele encoding threonine (T663, AT/TT). We sought to determine the influence of genetic variation at position 663 of ENaC on exhaled Na+ in healthy humans. Exhaled Na+ was measured in 18 AA and 13 AT/TT subjects (age=27±8 vs. 30±10yrs., ht.=174±12 vs. 171±10cm., wt=68±12 vs. 73±14kg., BMI=22±3 vs. 25±4kg/m2, mean±SD, for AA and AT/TT, respectively). Measurements were made at baseline and at 30, 60 and 90 minutes following the administration of a nebulized β2-agonist (albuterol sulfate, 2.5mg diluted in 3ml normal saline). The AA group had a higher baseline level of exhaled Na+ and a greater response to β2-agonist stimulation (baseline= 3.1±1.8 vs. 2.3±1.5mmol/l; 30min-post= 2.1±0.7 vs. 2.2±0.8mmol/l; 60min-post= 2.0±0.5 vs. 2.3±1.0mmol/l; 90min-post= 1.8±0.8 vs. 2.6±1.5mmol/l, mean±SD, for AA and AT/TT, respectively, p<0.05). The results are consistent with the notion that genetic variation of ENaC influences β2-adrenergic receptor stimulated Na+ clearance in the lungs, as there was a significant reduction in exhaled Na+ over time in the AA group.

Exhaled Breath Condensate Detects Baseline Reductions in Chloride and Increases in Response to Albuterol in Cystic Fibrosis Patients

“…The changes in EBC Na + and Cl − in response to albuterol were not the same between CF subjects and healthy subjects, and previous work found that isotonic saline does not mediate the improvements in MCC that hypertonic saline demonstrates in CF patients, suggesting that the changes in EBC Cl − we observed were not due to saline alone, but also adrenergic stimulation. When we compared EBC Na + concentrations based on a single nucleotide polymorphism gene encoding ENaC in healthy individuals, we found that individuals with the channel characterized by greater basal activity had lower baseline EBC Na + , which we feel adds support to the validity of this technique 64. Additionally, the difference in the baseline values within the healthy subjects between the saline and albuterol visits highlights the need for correcting for dilution of the ASL droplet by water vapor during exhalation.…”

“…When we compared EBC Na + concentrations based on a single nucleotide polymorphism gene encoding ENaC in healthy individuals, we found that individuals with the channel characterized by greater basal activity had lower baseline EBC Na + , which we feel adds support to the validity of this technique. 64 Additionally, the difference in the baseline values within the healthy subjects between the saline and albuterol visits highlights the need for correcting for dilution of the ASL droplet by water vapor during exhalation.…”

Epithelial sodium channel (ENaC) family: Phylogeny, structure–function, tissue distribution, and associated inherited diseases

“…The αA663 variant reduces ENaC activity and functional expression in Xenopus oocytes (Samaha et al, 2004; Tong et al, 2006), but the change in activity was opposite of that predicted by the results of Ambrosius et al Furthermore, no association was found between αT663A variant and blood pressure in a sample of 247 Japanese hypertensives (Sugiyama et al, 2001). Nonetheless, homozygous A663 allele appears to have a differential effect on lung function (Foxx-Lupo et al, 2011). …”

Genetic Variation of SCNN1A Influences Lung Diffusing Capacity in Cystic Fibrosis

“…Healthy individuals with the αA663 ENaC variant demonstrated a greater increase in lung diffusing capacity in response to exercise as compared to those with at least one copy of the αT663 variant (3). Additionally, in response to albuterol, an exogenous β 2 -receptor agonist, individuals with the αA663 ENaC variant had less Na + in their exhaled breath condensate 90 minutes after beta 2 -agonist administration as compared to those with the αT663 ENaC variant, suggesting a greater removal of Na + from the airways following activation (14). …”