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.

Advanced Lung Disease and Transplant Program Inova Fairfax Hospital Falls Church Virginia

Alfred Hospital and Monash University Melbourne Australia

Asan Medical Center University of Ulsan College of Medicine Seoul Korea

Biomedical Genomics Center University of Minnesota; Minneapolis Minnesota; and

Biomedical Research Centre University of Nottingham Nottingham United Kingdom

Brigham and Women's Hospital Harvard School of Medicine Boston Massachusetts

CardioPulmonary Reserach Center Alliance Pulmonary Group Guaynabo Puerto Rico

Centre for Cell Therapy and Regenerative Medicine School of Biomedical Sciences The University of Western Australia Perth Australia

Cork University Hospital and University College Cork Cork Ireland

Department of Diseases of the Thorax Ospedale GB Morgagni Forlì Italy

Department of Immunology University of Colorado Denver Denver Colorado

Department of Internal Medicine University of Genoa Genoa Italy

Department of Medicine and

Department of Medicine Columbia University Irving Medical Center New York New York

Department of Medicine Tallaght University Hospital Trinity College Dublin Dublin Ireland

Department of Medicine University of Alabama at Birmingham Birmingham Alabama

Department of Medicine University of California San Francisco San Francisco California

Department of Medicine University of Chicago Chicago Illinois

Department of Medicine University of Virginia Charlottesville Virginia

Department of Medicine Vanderbilt University School of Medicine Nashville Tennessee

Department of Medicine Warren Alpert Medical School of Brown University Providence Rhode Island

Department of Pulmonary Medicine Gazi University School of Medicine Ankara Turkey

Department of Pulmonology Ege University Hospital Bornova Izmir Turkey

Department of Respiratory Diseases and Allergy Aarhus University Hospital Aarhus Denmark

Department of Respiratory Medicine 1st Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic

Division of Pulmonary and Critical Care Medicine Massachusetts General Hospital Boston Massachusetts

Gilead Sciences Foster City California

Helmholtz Zentrum München Neuherberg Germany

Institute for Respiratory Health and

Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas México City México

MRC Centre for Inflammation Research University of Edinburgh Edinburgh United Kingdom

National Hospital Organization Kinki Chuo Chest Medical Center Osaka Japan

National Hospital Organization Tokyo National Hospital Tokyo Japan

National Jewish Health Denver Colorado

National University Hospital of Iceland University of Iceland Reykjavik Iceland

Northwest Genomics Center University of Washington Seattle Washington

Oklahoma Medical Research Foundation Oklahoma City Oklahoma

Perelman School of Medicine at the University of Pennsylvania Philadelphia Pennsylvania

Pulmonary Medicine GB Morgagni Hospital Forlì Italy

Respiratory Department University Hospital of Bellvitge University of Barcelona Barcelona Spain

Respiratory Medicine Unit Royal Infirmary of Edinburgh Edinburgh United Kingdom

Royal Brompton Hospital and Imperial College London United Kingdom

Royal Papworth Hospital and Cambridge University Hospitals NHS Foundation Trust Cambridge United Kingdom

Royal Prince Alfred Hospital and University of Sydney Sydney Australia

Ruhrlandklinik University Hospital University of Duisburg Essen Essen Germany

School of Medicine University College Dublin Dublin Ireland

School of Public Health

Simmons Center for Interstitial Lung Disease University of Pittsburgh Pittsburgh Pennsylvania

St Vincent's University Hospital Dublin Ireland

Tokyo Medical and Dental University Tokyo Japan

Universidad Nacional Autónoma de México México City México

Université Paris Diderot and Hôpital Bichat Paris France

University Hospital Munich Munich Germany

University of British Columbia Vancouver Canada

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Am J Respir Crit Care Med. 2019 Jul 15;200(2):125-127. doi: 10.1164/rccm.201905-0925ED. PubMed

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Martinez FJ, Collard HR, Pardo A, Raghu G, Richeldi L, Selman M, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis Primers. 2017;3:17074. PubMed

Nogee LM, Dunbar AE, III, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001;344:573–579. PubMed

Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356:1317–1326. PubMed

Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009;84:52–59. PubMed PMC

Stuart BD, Choi J, Zaidi S, Xing C, Holohan B, Chen R, et al. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat Genet. 2015;47:512–517. PubMed PMC

Fingerlin TE, Murphy E, Zhang W, Peljto AL, Brown KK, Steele MP, et al. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet. 2013;45:613–620. PubMed PMC

Noth I, Zhang Y, Ma SF, Flores C, Barber M, Huang Y, et al. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study. Lancet Respir Med. 2013;1:309–317. PubMed PMC

Fingerlin TE, Zhang W, Yang IV, Ainsworth HC, Russell PH, Blumhagen RZ, et al. Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet. 2016;17:74. PubMed PMC

Allen RJ, Porte J, Braybrooke R, Flores C, Fingerlin TE, Oldham JM, et al. Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study. Lancet Respir Med. 2017;5:869–880. PubMed PMC

Wang C, Zhuang Y, Guo W, Cao L, Zhang H, Xu L, et al. Mucin 5B promoter polymorphism is associated with susceptibility to interstitial lung diseases in Chinese males. PLoS One. 2014;9:e104919. PubMed PMC

Horimasu Y, Ohshimo S, Bonella F, Tanaka S, Ishikawa N, Hattori N, et al. MUC5B promoter polymorphism in Japanese patients with idiopathic pulmonary fibrosis. Respirology. 2015;20:439–444. PubMed

Dressen A, Abbas AR, Cabanski C, Reeder J, Ramalingam TR, Neighbors M, et al. Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study. Lancet Respir Med. 2018;6:603–614. PubMed PMC

Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. Diagnosis of idiopathic pulmonary fibrosis: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198:e44–e68. PubMed

Lee S, Emond MJ, Bamshad MJ, Barnes KC, Rieder MJ, Nickerson DA, et al. NHLBI GO Exome Sequencing Project—ESP Lung Project Team. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet. 2012;91:224–237. PubMed PMC

Comprehensive R Archive Network. SKAT: SNP-Set (Sequence) Kernel Association Test. 2017 [accessed 2018 Sept 1]. Available from: https://cran.r-project.org/web/packages/SKAT/index.html.

Zerbino DR, Achuthan P, Akanni W, Amode MR, Barrell D, Bhai J, et al. Ensembl 2018. Nucleic Acids Res. 2018;46:D754–D761. PubMed PMC

Cingolani P, Platts A, Wang L, Coon M, Nguyen T, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 2012;6:80–92. PubMed PMC

Battle A, Brown CD, Engelhardt BE, Montgomery SB GTEx Consortium; Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group; Statistical Methods Groups—Analysis Working Group; Enhancing GTEx (eGTEx) Groups; NIH Common Fund; NIH/NCI; NIH/NHGRI; NIH/NIMH; NIH/NIDA; Biospecimen Collection Source Site—NDRI; Biospecimen Collection Source Site—RPCI; Biospecimen Core Resource—VARI; Brain Bank Repository—University of Miami Brain Endowment Bank; Leidos Biomedical—Project Management; ELSI Study; Genome Browser Data Integration &Visualization—EBI; Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz; Lead analysts; Laboratory, Data Analysis &Coordinating Center (LDACC); NIH Program Management; Biospecimen Collection; Pathology; eQTL Manuscript Working Group. Genetic effects on gene expression across human tissues. Nature. 2017;550:204–213. [Published erratum appears in Nature 553:530.] PubMed

Mathai SK, Pedersen BS, Smith K, Russell P, Schwarz MI, Brown KK, et al. Desmoplakin variants are associated with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2016;193:1151–1160. PubMed PMC

Bierne H, Tham TN, Batsche E, Dumay A, Leguillou M, Kernéis-Golsteyn S, et al. Human BAHD1 promotes heterochromatic gene silencing. Proc Natl Acad Sci USA. 2009;106:13826–13831. PubMed PMC

Lebreton A, Lakisic G, Job V, Fritsch L, Tham TN, Camejo A, et al. A bacterial protein targets the BAHD1 chromatin complex to stimulate type III interferon response. Science. 2011;331:1319–1321. PubMed

Hobbs BD, de Jong K, Lamontagne M, Bossé Y, Shrine N, Artigas MS, et al. COPDGene Investigators; ECLIPSE Investigators; LifeLines Investigators; SPIROMICS Research Group; International COPD Genetics Network Investigators; UK BiLEVE Investigators; International COPD Genetics Consortium. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis. Nat Genet. 2017;49:426–432. PubMed PMC

Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci USA. 2007;104:7552–7557. PubMed PMC

Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364:1503–1512. PubMed PMC

Helling BA, Gerber AN, Kadiyala V, Sasse SK, Pedersen BS, Sparks L, et al. Regulation of MUC5B expression in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 2017;57:91–99. PubMed PMC

Evans CM, Fingerlin TE, Schwarz MI, Lynch D, Kurche J, Warg L, et al. Idiopathic pulmonary fibrosis: a genetic disease that involves mucociliary dysfunction of the peripheral airways. Physiol Rev. 2016;96:1567–1591. PubMed PMC

Hancock LA, Hennessy C, Solomon GM, Dobrinskikh E, Estrella A, Hara N, et al. Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice. Nat Commun. 2018;9:5363. PubMed PMC

Nakano Y, Yang IV, Walts AD, Watson AM, Helling BA, Fletcher AA, et al. MUC5B promoter variant rs35705950 affects MUC5B expression in the distal airways in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2016;193:464–466. PubMed PMC

Button B, Cai LH, Ehre C, Kesimer M, Hill DB, Sheehan JK, et al. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science. 2012;337:937–941. PubMed PMC

Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants