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Am J Respir Crit Care Med. 2017 Jul 1;196(1):82-93. doi: 10.1164/rccm.201610-2088OC.

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

Author information

1
1 Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.
2
2 Department of Medicine, Austin Health and Royal Melbourne Hospital, The University of Melbourne, Melbourne, Victoria, Australia.
3
3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
4
4 Duke Clinical Research Institute, Durham, North Carolina.
5
5 Gilead Sciences, Foster City, California.
6
6 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; and.
7
7 Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.

Abstract

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.

KEYWORDS:

collapsing analysis; exome sequencing; genetics; interstitial lung disease; pulmonary fibrosis

PMID:
28099038
PMCID:
PMC5519963
DOI:
10.1164/rccm.201610-2088OC
[Indexed for MEDLINE]
Free PMC Article

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