An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.


Journal Article

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology. OBJECTIVES: The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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). CONCLUSIONS: 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.

Full Text

Duke Authors

Cited Authors

  • Petrovski, S; Todd, JL; Durheim, MT; Wang, Q; Chien, JW; Kelly, FL; Frankel, C; Mebane, CM; Ren, Z; Bridgers, J; Urban, TJ; Malone, CD; Finlen Copeland, A; Brinkley, C; Allen, AS; O'Riordan, T; McHutchison, JG; Palmer, SM; Goldstein, DB

Published Date

  • July 1, 2017

Published In

Volume / Issue

  • 196 / 1

Start / End Page

  • 82 - 93

PubMed ID

  • 28099038

Pubmed Central ID

  • 28099038

Electronic International Standard Serial Number (EISSN)

  • 1535-4970

Digital Object Identifier (DOI)

  • 10.1164/rccm.201610-2088OC


  • eng

Conference Location

  • United States