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Title: An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.
Austin Authors: Petrovski, Slavé;Todd, Jamie L;Durheim, Michael T;Wang, Quanli;Chien, Jason W;Kelly, Fran L;Frankel, Courtney;Mebane, Caroline M;Ren, Zhong;Bridgers, Joshua;Urban, Thomas J;Malone, Colin D;Finlen Copeland, Ashley;Brinkley, Christie;Allen, Andrew S;O'Riordan, Thomas;McHutchison, John G;Palmer, Scott M;Goldstein, David B
Affiliation: Gilead Sciences, Foster City, California
Duke Clinical Research Institute, Durham, North Carolina
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Institute for Genomic Medicine, Columbia University Medical Center, New York, New York
Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
Division of Pharmacotherapy and Experimental Therapeutics, Center for Pharmacogenomics and Individualized Therapy, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
Institute for Genomic Medicine, Columbia University Medical Center, New York, New York, USA
Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia
Issue Date: 1-Jul-2017
Publication information: American Journal of Respiratory and Critical Care Medicine 2017; 196(1): 82-93
Abstract: Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology. The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis. We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis. We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P < 4.5 × 10-7) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10-22). We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.
DOI: 10.1164/rccm.201610-2088OC
ORCID: 0000-0002-1527-961X
Journal: American Journal of Respiratory and Critical Care Medicine
PubMed URL: 28099038
Type: Journal Article
Subjects: collapsing analysis
exome sequencing
interstitial lung disease
pulmonary fibrosis
Appears in Collections:Journal articles

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