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

• Published in: American journal of respiratory and critical care medicine Vol. 200; no. 2; pp. 199 - 208
• Main Authors: Blumhagen, Rachel Z, Yang, Ivana V, Walts, Avram, Powers, Julie, Bishop, Makenna, Russell, Pamela, Vestal, Brian, Cardwell, Jonathan, Markin, Cheryl R, Mathai, Susan K, Schwarz, Marvin I, Steele, Mark P, Lee, Joyce, Brown, Kevin K, Loyd, James E, Crapo, James D, Silverman, Edwin K, Cho, Michael H, James, Judith A, Guthridge, Joel M, Cogan, Joy D, Kropski, Jonathan A, Swigris, Jeffrey J, Bair, Carol, Kim, Dong Soon, Ji, Wonjun, Kim, Hocheol, Song, Jin Woo, Maier, Lisa A, Hirani, Nikhil, Poon, Azin S, Li, Feng, Braybrooke, Rebecca, Saini, Gauri, Molyneaux, Philip L, Saunders, Peter, Zhang, Yingze, Kass, Daniel J, Rojas, Mauricio, Wolters, Paul J, Collard, Harold R, Sundy, John S, O'Riordan, Thomas, Strek, Mary E, Noth, Imre, Ma, Shwu-Fan, Porteous, Mary K, Kreider, Maryl E, Patel, Namrata B, Hirose, Masaki, Arai, Toru, Akagawa, Shinobu, Behr, Jürgen, Mogulkoc, Nesrin, Corte, Tamera J, Glaspole, Ian, Tomassetti, Sara, Ravaglia, Claudia, Crestani, Bruno, Borie, Raphael, Parfrey, Helen, Fiddler, Christine, Rassl, Doris, Molina-Molina, Maria, Worboys, Ana Montes, Gudmundsson, Gunnar, Podolanczuk, Anna J, Montesi, Sydney B, Bendstrup, Elisabeth, Danchel, Vivi, Pardo, Annie, Keane, Michael P, Doran, Peter, Vašáková, Martina, Sterclova, Martina, Ryerson, Christopher J, Wilcox, Pearce G, Okamoto, Tsukasa, Miyazaki, Yasunari, Laurent, Geoffrey, Prele, Cecilia, Moodley, Yuben, Shea, Barry S, Suzukawa, Maho, Narumoto, Osamu, Nathan, Steven D, Venuto, Drew C, Woldehanna, Merte L, de Andrade, Joao A, Luckhardt, Tracy, Kulkarni, Tejaswini, Bonella, Francesco, Donnelly, Seamus C, McElroy, Aoife, Aranda, Alvaro, Carbone, Roberto G, Puppo, Francesco, Nickerson, Deborah A, Fingerlin, Tasha E, Schwartz, David A
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 15.07.2019
• Subjects: ATP-Binding Cassette Transporters - genetics; Case-Control Studies; Cellular Senescence - genetics; DNA Helicases - genetics; Exoribonucleases - genetics; Family medical history; Female; Gene loci; Genealogy; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genomes; Genomics; GTPase-Activating Proteins - genetics; High-Throughput Nucleotide Sequencing; Hospitals; Host-Pathogen Interactions - genetics; Humans; Idiopathic Pulmonary Fibrosis - genetics; Logistic Models; Lung diseases; Male; Medicine; Mucin-5B - genetics; Mutation; Original; Promoter Regions, Genetic - genetics; Pulmonary fibrosis; Pulmonary Surfactant-Associated Protein A - genetics; Pulmonary Surfactant-Associated Protein C - genetics; RNA - genetics; Senescence; Sequence Analysis, DNA; Telomerase - genetics; Telomere-Binding Proteins - genetics; University colleges; New York; United Kingdom > UK; United States > US; Japan; Oklahoma; California; Iceland; Pennsylvania; San Francisco California; Turkey; Ireland; Colorado; Massachusetts; Italy; Virginia; Aarhus Denmark; Germany; genetic variants; rare variants; idiopathic pulmonary fibrosis; targeted resequencing; disease risk alleles
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.201810-1891OC

Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. 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. We performed deep targeted resequencing (3.69 Mb of DNA) in cases (  = 3,624) and control subjects (  = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and ) individual common variants via logistic regression and ) groups of rare variants via sequence kernel association tests. 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 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 (  = 9.60 × 10 ). In addition to identifying for the first time that rare variation in is associated with disease, we confirmed the role of rare variation in the and gene regions in the risk of IPF, and found that the and regions have independent common and rare variant signals. 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.