Slavé Petrovski1,2, Jamie L Todd3,4, Michael T Durheim3,4, Quanli Wang1, Jason W Chien5, Fran L Kelly3, Courtney Frankel3, Caroline M Mebane1, Zhong Ren1, Joshua Bridgers1, Thomas J Urban6, Colin D Malone1, Ashley Finlen Copeland3, Christie Brinkley3, Andrew S Allen7, Thomas O'Riordan5, John G McHutchison5, Scott M Palmer3,4, David B Goldstein1. 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.
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.
Authors: Caroline Kannengiesser; Raphael Borie; Christelle Ménard; Marion Réocreux; Patrick Nitschké; Steven Gazal; Hervé Mal; Camille Taillé; Jacques Cadranel; Hilario Nunes; Dominique Valeyre; Jean François Cordier; Isabelle Callebaut; Catherine Boileau; Vincent Cottin; Bernard Grandchamp; Patrick Revy; Bruno Crestani Journal: Eur Respir J Date: 2015-05-28 Impact factor: 16.671
Authors: Sofya Tokman; Jonathan P Singer; Megan S Devine; Glen P Westall; John-David Aubert; Michael Tamm; Gregory I Snell; Joyce S Lee; Hilary J Goldberg; Jasleen Kukreja; Jeffrey A Golden; Lorriana E Leard; Christine K Garcia; Steven R Hays Journal: J Heart Lung Transplant Date: 2015-05-11 Impact factor: 10.247
Authors: Richard D Bagnall; Douglas E Crompton; Slavé Petrovski; Lien Lam; Carina Cutmore; Sarah I Garry; Lynette G Sadleir; Leanne M Dibbens; Anita Cairns; Sara Kivity; Zaid Afawi; Brigid M Regan; Johan Duflou; Samuel F Berkovic; Ingrid E Scheffer; Christopher Semsarian Journal: Ann Neurol Date: 2016-02-02 Impact factor: 10.422
Authors: Adam Auton; Lisa D Brooks; Richard M Durbin; Erik P Garrison; Hyun Min Kang; Jan O Korbel; Jonathan L Marchini; Shane McCarthy; Gil A McVean; Gonçalo R Abecasis Journal: Nature Date: 2015-10-01 Impact factor: 49.962
Authors: Tasha E Fingerlin; Elissa Murphy; Weiming Zhang; Anna L Peljto; Kevin K Brown; Mark P Steele; James E Loyd; Gregory P Cosgrove; David Lynch; Steve Groshong; Harold R Collard; Paul J Wolters; Williamson Z Bradford; Karl Kossen; Scott D Seiwert; Roland M du Bois; Christine Kim Garcia; Megan S Devine; Gunnar Gudmundsson; Helgi J Isaksson; Naftali Kaminski; Yingze Zhang; Kevin F Gibson; Lisa H Lancaster; Joy D Cogan; Wendi R Mason; Toby M Maher; Philip L Molyneaux; Athol U Wells; Miriam F Moffatt; Moises Selman; Annie Pardo; Dong Soon Kim; James D Crapo; Barry J Make; Elizabeth A Regan; Dinesha S Walek; Jerry J Daniel; Yoichiro Kamatani; Diana Zelenika; Keith Smith; David McKean; Brent S Pedersen; Janet Talbert; Raven N Kidd; Cheryl R Markin; Kenneth B Beckman; Mark Lathrop; Marvin I Schwarz; David A Schwartz Journal: Nat Genet Date: 2013-04-14 Impact factor: 38.330
Authors: Leann L Silhan; Pali D Shah; Daniel C Chambers; Laurie D Snyder; Gerdt C Riise; Christa L Wagner; Eva Hellström-Lindberg; Jonathan B Orens; Juliette F Mewton; Sonye K Danoff; Murat O Arcasoy; Mary Armanios Journal: Eur Respir J Date: 2014-05-15 Impact factor: 16.671
Authors: Chad A Newton; David Zhang; Justin M Oldham; Julia Kozlitina; Shwu-Fan Ma; Fernando J Martinez; Ganesh Raghu; Imre Noth; Christine Kim Garcia Journal: Am J Respir Crit Care Med Date: 2019-08-01 Impact factor: 21.405
Authors: Sophia Cameron-Christie; Charles J Wolock; Emily Groopman; Slavé Petrovski; Sitharthan Kamalakaran; Gundula Povysil; Dimitrios Vitsios; Mengqi Zhang; Jan Fleckner; Ruth E March; Sahar Gelfman; Maddalena Marasa; Yifu Li; Simone Sanna-Cherchi; Krzysztof Kiryluk; Andrew S Allen; Bengt C Fellström; Carolina Haefliger; Adam Platt; David B Goldstein; Ali G Gharavi Journal: J Am Soc Nephrol Date: 2019-05-13 Impact factor: 10.121
Authors: Jonathan A Kropski; Sara Reiss; Cheryl Markin; Kevin K Brown; David A Schwartz; Marvin I Schwarz; James E Loyd; John A Phillips; Timothy S Blackwell; Joy D Cogan Journal: Am J Respir Crit Care Med Date: 2017-12-01 Impact factor: 21.405
Authors: Chad A Newton; Justin M Oldham; Brett Ley; Vikram Anand; Ayodeji Adegunsoye; Gabrielle Liu; Kiran Batra; Jose Torrealba; Julia Kozlitina; Craig Glazer; Mary E Strek; Paul J Wolters; Imre Noth; Christine Kim Garcia Journal: Eur Respir J Date: 2019-04-11 Impact factor: 16.671
Authors: Xiaomu Wei; M Nieves Calvo-Vidal; Siwei Chen; Gang Wu; Maria V Revuelta; Jian Sun; Jinghui Zhang; Michael F Walsh; Kim E Nichols; Vijai Joseph; Carrie Snyder; Celine M Vachon; James D McKay; Shu-Ping Wang; David S Jayabalan; Lauren M Jacobs; Dina Becirovic; Rosalie G Waller; Mykyta Artomov; Agnes Viale; Jayeshkumar Patel; Jude Phillip; Selina Chen-Kiang; Karen Curtin; Mohamed Salama; Djordje Atanackovic; Ruben Niesvizky; Ola Landgren; Susan L Slager; Lucy A Godley; Jane Churpek; Judy E Garber; Kenneth C Anderson; Mark J Daly; Robert G Roeder; Charles Dumontet; Henry T Lynch; Charles G Mullighan; Nicola J Camp; Kenneth Offit; Robert J Klein; Haiyuan Yu; Leandro Cerchietti; Steven M Lipkin Journal: Cancer Res Date: 2018-03-20 Impact factor: 12.701