Variation in Cilia Protein Genes and Progression of Lung Disease in Cystic Fibrosis

Elizabeth Blue, Tin L Louie, Jessica X Chong, Scott J Hebbring, Kathleen C Barnes, Nicholas M Rafaels, Michael R Knowles, Ronald L Gibson, Michael J Bamshad, Mary J Emond

Cystic fibrosis, like primary ciliary dyskinesia, is an autosomal recessive disorder characterized by abnormal mucociliary clearance and obstructive lung disease. We hypothesized that genes underlying the development or function of cilia may modify lung disease severity in persons with cystic fibrosis. To test this hypothesis, we compared variants in 93 candidate genes in both upper and lower tertiles of lung function in a large cohort of children and adults with cystic fibrosis to a population control data set. Variants within candidate genes were tested for association using the SKAT-O test, comparing cystic fibrosis cases defined by poor (n=127) or preserved (n=127) lung function to population controls (n= 3269 or 3148, respectively). Associated variants were then tested for association with related phenotypes in independent data sets. Variants in DNAH14 and DNAAF3 were associated with poor lung function in cystic fibrosis, while variants in DNAH14 and DNAH6 were associated with preserved lung function in cystic fibrosis. Association between DNAH14 and lung function were replicated in disease-related phenotypes characterized by obstructive lung disease in adults. Genetic variants within DNAH6, DNAH14, and DNAAF3 are associated with variation in lung function among person with cystic fibrosis.