We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.
- Authors
Petrovski, Slavé; Todd, Jamie L.; Durheim, Michael T.; Quanli Wang; Chien, Jason W.; Kelly, Fran L.; Frankel, Courtney; Mebane, Caroline M.; Zhong Ren; Bridgers, Joshua; Urban, Thomas J.; Malone, Colin D.; Copeland, Ashley Finlen; Brinkley, Christie; Allen, Andrew S.; O'Riordan, Thomas; McHutchison, John G.; Palmer, Scott M.; Goldstein, David B.; Wang, Quanli
- Abstract
<bold>Rationale: </bold>Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology.<bold>Objectives: </bold>The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis.<bold>Methods: </bold>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.<bold>Measurements and Main Results: </bold>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).<bold>Conclusions: </bold>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.
- Subjects
DISEASE susceptibility; GENETICS; GENOMES; RESEARCH funding; IDIOPATHIC pulmonary fibrosis
- Publication
American Journal of Respiratory & Critical Care Medicine, 2017, Vol 196, Issue 1, p82
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201610-2088OC