Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis
Authors: Camille Moore, Rachel Z. Blumhagen, Ivana V. Yang, Avram Walts, Julie Powers, Tarik Walker, Makenna Bishop, Pamela Russell, Brian Vestal, Jonathan Cardwell, Cheryl R. 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, Hocheol Kim, Jin Woo Song, Lisa A. Maier, Karin A. Pacheco, Nikhil Hirani, Azin S. Poon, Feng Li, R. 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 O’Riordan, Mary E. Strek, Imre Noth, Shwu-Fan Ma, Mary K. Porteous, Maryl E. Kreider, Namrata B. Patel, Yoshikazu Inoue, Masaki Hirose, Toru Arai, Shinobu Akagawa, Oliver Eickelberg, Isis Enlil Fernandez, Jürgen Behr, Nesrin Mogulkoc, Tamera J. Corte, Ian Glaspole, Sara Tomassetti, Claudia Ravaglia, Venerino Poletti, Bruno Crestani, Raphael Borie, Caroline Kannengiesser, Helen Parfrey, Christine Fiddler, Doris Rassl, Maria Molina-Molina, Carlos Machahua, Ana Montes Worboys, Gunnar Gudmundsson, Helgi J. Isaksson, David J. Lederer, Anna J. Podolanczuk, Sydney B. Montesi, Elisabeth Bendstrup, Vivi Danchel, Moises Selman, Annie Pardo, Michael T. Henry, Michael P. Keane, Peter Doran, Martina Vašáková, Martina Sterclova, Christopher J. Ryerson, Pearce G. Wilcox, Tsukasa Okamoto, Haruhiko Furusawa, Yasunari Miyazaki, Geoffrey Laurent, Svetlana Baltic, Cecilia Prele, Yuben Moodley, Barry S. Shea, Ken Ohta, Maho Suzukawa, Osamu Narumoto, Steven D. Nathan, Drew C. Venuto, Merte L. Woldehanna, Nurdan Kokturk, Joao A. de Andrade, Tracy Luckhardt, Tejaswini Kulkarni, Francesco Bonella, Seamus C. Donnelly, Aoife McElroy, Michelle E. Armstong, Alvaro Aranda, Roberto G. Carbone, Francesco Puppo, Kenneth B. Beckman, Deborah A. Nickerson, Tasha E. Fingerlin, David A. Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

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.