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Ann Am Thorac Soc. 2018 Apr;15(4):440-448. doi: 10.1513/AnnalsATS.201706-451OC.

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

Author information

1
1 Division of Medical Genetics.
2
2 Department of Biostatistics.
3
3 Department of Pediatrics, and.
4
4 Center for Human Genetics, Marshfield Clinic, Marshfield, Wisconsin.
5
5 Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, Colorado.
6
6 Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and.
7
7 Division of Pulmonary Medicine; and.
8
8 Department of Genome Sciences, University of Washington, Seattle, Washington.
9
9 Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington.

Abstract

RATIONALE:

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.

OBJECTIVES:

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 with those of a population control dataset.

METHODS:

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 with population controls (n = 3,269 or 3,148, respectively). Associated variants were then tested for association with related phenotypes in independent datasets.

RESULTS:

Variants in DNAH14 and DNAAF3 were associated with poor lung function in cystic fibrosis, whereas variants in DNAH14 and DNAH6 were associated with preserved lung function in cystic fibrosis. Associations between DNAH14 and lung function were replicated in disease-related phenotypes characterized by obstructive lung disease in adults.

CONCLUSIONS:

Genetic variants within DNAH6, DNAH14, and DNAAF3 are associated with variation in lung function among persons with cystic fibrosis.

KEYWORDS:

ciliary motility disorders; cystic fibrosis; genetic association studies; respiratory function tests

PMID:
29323929
PMCID:
PMC5879139
[Available on 2019-04-01]
DOI:
10.1513/AnnalsATS.201706-451OC

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