Association of Genetic Variation and Exercise Capacity with Clinical Indicators of Disease in Cystic Fibrosis

Abstract

Introduction Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), which results in ion dysregulation and mucous buildup, most notably in the lungs. Previously a childhood disease, advancement in treatment options has greatly improved clinical course leading to longer lifespans. This progress has created a need for more sensitive clinical measures and personalized medicine options. Exploring genetic modifiers of disease along with response to exercise would provide valuable and unique information, contributing to better, more personalized assessment and management of disease. Purpose The purpose of this dissertation is two-fold. The first aim was to explore the impact of genetic variation at amino acid 663 of the sodium channel epithelial 1 alpha gene (SCNN1A) on clinical features of CF. In Study One it was hypothesized that subjects with at least one copy of the gain-of-function variant T663 (AT/TT) would have poorer clinical outcomes than those homozygous for the wild-type variant A663 (AA). In studies Two and Three the primary aim was to examine the clinical value of the six-minute walk test (6MWT) and one-minute sit-to-stand test (1STS) in the management of CF. It was hypothesized that response to the 6MWT and 1STS would be strongly correlated and measures from each test would be associated with clinical outcomes of disease. Methods Thirty-five CF subjects were enrolled and all had at least one copy of the F508del mutation. Buccal swabs were collected and samples were analyzed for genetic variation at position 663 of the SCNN1A gene (AA, AT/TT). The 6MWT and 1STS were performed. Continuous monitoring of heart rate (HR) and peripheral blood oxygen saturation (SpO2) was taken during exercise testing. The desaturation-distance ratio (DDR) was calculated using SpO2 measures and six-minute walk distance (6MWD). Medical charts were reviewed for pulmonary function and indicators of disease status. Depending on distribution of data, independent Student’s t-test or Mann Whitney U test was used to compare means. Correlations were performed using Spearman test and Fisher’s exact test was used to analyze categorical variables. Cox regression was used to assess days to pulmonary exacerbation. All data are presented as mean ± standard deviation unless otherwise noted. Significance was set at 0.05. Results There were no statistically significant differences in clinical outcomes between the AA and AT/TT genotypes. Clinically relevant observations in regards to lung function over time and exercise performance were noted and warrant further research. Further, 6MWD and 1STS repetitions were significantly correlated but neither outcome correlated with measures of pulmonary function. However, DDR was significantly correlated with several measures of pulmonary function, suggesting it is a better indicator of lung function than 6MWD alone. Additionally, those who desaturated during the 1STS (change in SpO2 > 4% from rest) had significantly lower lung function compared to those who did not. Neither 6MWD nor 1STS repetitions was associated with pulmonary exacerbation during follow-up. Those who experienced a pulmonary exacerbation during follow-up had significantly greater DDR compared to those who did not have an exacerbation. Conclusions Variation at position 663 of the SCNN1A gene may modify pulmonary disease in patients with CF, though further research is needed. Additionally, the 6MWT and 1STS show promise in providing unique and meaningful information about CF disease and, used in conjunction with typical 6MWT outcomes, DDR may be a helpful tool in evaluating exercise capacity in patients with CF.