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Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis

2019; American Thoracic Society; Volume: 200; Issue: 2 Linguagem: Inglês

10.1164/rccm.201810-1891oc

1535-4970

Camille M. Moore, Rachel Z. Blumhagen, Ivana V. Yang, Avram Walts, Julie Powers, Tarik Walker, Makenna Bishop, Pamela Russell, Brian Vestal, Jonathan Cardwell, Cheryl Markin, Susan K. Mathai, Marvin I. Schwarz, Mark P. Steele, Joyce Lee, Kevin K. Brown, James E. Loyd, James D. Crapo, Edwin K. Silverman, Michael H. Cho, Judith A. James, Joel M. Guthridge, Joy D. Cogan, Jonathan A. Kropski, Jeffrey J. Swigris, Carol Bair, Dong Soon Kim, Wonjun Ji, Ho Cheol Kim, Jin Woo Song, Lisa A. Maier, Karin Pacheco, Nikhil Hirani, Azin Poon, Feng Li, Gisli Jenkins, Rebecca Braybrooke, Gauri Saini, Toby M. Maher, Philip L. Molyneaux, Peter Saunders, Yingze Zhang, Kevin F. Gibson, Daniel J. Kass, Mauricio Rojas, John Sembrat, Paul J. Wolters, Harold R. Collard, John S. Sundy, Thomas G. O’Riordan, Mary E. Strek, Imre Noth, Shwu‐Fan Ma, Mary K. Porteous, Maryl Kreider, Namrata Patel, Yoshikazu Inoue, Masaki Hirose, Toru Arai, Shinobu Akagawa, Oliver Eickelberg, Isis E. Fernandez, Jürgen Behr, Nesrin Moğulkoç, Tamera J. Corte, Ian Glaspole, Sara Tomassetti, Claudia Ravaglia, Venerino Poletti, Bruno Crestani, Raphaël Borie, Caroline Kannengiesser, Helen Parfrey, Christine Fiddler, Doris M. Rassl, María Molina‐Molina, Carlos Machahua, Ana Montes Worboys, Gunnar Guðmundsson, Helgi J. Ísaksson, David J. Lederer, Anna J. Podolanczuk, Sydney B. Montesi, Elisabeth Bendstrup, Vivi Danchel, Moisés Selman, Annie Pardo, Michael T. Henry, Michael P. Keane, Peter Doran, Martina Vašáková, Martina Šterclová, Christopher J. Ryerson, Pearce Wilcox, Tsukasa Okamoto, Haruhiko Furusawa, Yasunari Miyazaki, Geoffrey J. Laurent, Svetlana Baltic, Cecilia M. Prêle, Yuben Moodley, Barry S. Shea, Ken Ohta, Maho Suzukawa, Osamu Narumoto, Steven D. Nathan, D. Venuto, Merte Lemma WoldeHanna, Nurdan Köktürk, João A. de Andrade, Tracy Luckhardt, Tejaswini Kulkarni, Francesco Bonella, Seamus Donnelly, Aoife McElroy, Michelle E. Armstong, Alvaro U. Aranda, Roberto G. Carbone, Francesco Puppo, Kenneth B. Beckman, Deborah A. Nickerson, Tasha E. Fingerlin, David A. Schwartz,

Chronic Obstructive Pulmonary Disease (COPD) Research

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung.Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease.Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests.Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91–6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34–26.17) for two copies of the risk allele (P = 9.60 × 10−295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals.Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.