Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants.
| Title: | Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants. |
|---|---|
| Authors: | Peljto AL; Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.; Blumhagen RZ; Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.; National Jewish Health, Denver, Colorado.; Walts AD; National Jewish Health, Denver, Colorado.; Cardwell J; Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.; Powers J; Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.; Corte TJ; Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia.; Dickinson JL; Menzies Institute of Medical Research, University of Tasmania, Hobart, Tasmania, Australia.; Glaspole I; Allergy, Asthma and Clinical Immunology Clinic, Alfred Health, Sydney, Australia.; Moodley YP; Department of Respiratory Medicine, University of Western Australia, Perth, Australia.; Vasakova MK; Department of Respiratory Medicine, University Thomayer Hospital, Prague, Czech Republic.; Bendstrup E; Center for Rare Lung Diseases, Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark.; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Davidsen JR; South Danish Center for Interstitial Lung Diseases, Department of Respiratory Medicine, Odense University Hospital, Odense, Denmark.; Borie R; Service de Pneumologie A and.; Crestani B; Service de Pneumologie A and.; Université Paris Cité, INSERM, Physiopathologie et Épidémiologie des Maladies Respiratoires, Paris, France.; Dieude P; Service de Rhumatologie, Hopital Bichat, Paris, France.; Bonella F; Center for Interstitial and Rare Lung Diseases, Ruhrlandklinik University Hospital, University of Duisburg-Essen, Essen, Germany.; Costabel U; Center for Interstitial and Rare Lung Diseases, Ruhrlandklinik University Hospital, University of Duisburg-Essen, Essen, Germany.; Gudmundsson G; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.; Department of Respiratory Medicine and Sleep, Landspitali University Hospital, Reykjavik, Iceland.; Donnelly SC; Trinity College Dublin, Dublin, Ireland.; Egan J; National Lung Transplantation Centre, Mater Misericordiae University Hospital, Dublin, Ireland.; Henry MT; Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland.; Keane MP; St. Vincent's University Hospital, University College Dublin, Dublin, Ireland.; Kennedy MP; Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland.; McCarthy C; St. Vincent's University Hospital, University College Dublin, Dublin, Ireland.; McElroy AN; Trinity College Dublin, Dublin, Ireland.; Olaniyi JA; Trinity College Dublin, Dublin, Ireland.; O'Reilly KMA; Mater Misericordiae University Hospital, Dublin, Ireland.; Richeldi L; Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.; Università Cattolica del Sacro Cuore, Rome, Italy.; Leone PM; Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy.; Università Cattolica del Sacro Cuore, Rome, Italy.; Poletti V; Department of Diseases of the Thorax, G. B. Morgagni Hospital, Forlì, Italy.; Department of Medical and Surgical Sciences, DIMES University of Bologna, Bologna, Italy.; Puppo F; Department of Internal Medicine, University of Genoa, Genoa, Italy.; Tomassetti S; Department of Clinical and Experimental Medicine, Interventional Pulmonology Unit, Careggi University Hospital, Florence, Italy.; Luzzi V; Interventional Pulmonology Unit, Careggi University Hospital, Florence, Italy.; Kokturk N; Faculty of Medicine, Gazi University, Ankara, Turkey.; Mogulkoc N; Department of Pulmonology, Ege University Hospital, Izmir, Turkey.; Fiddler CA; Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom.; Hirani N; University of Edinburgh, Edinburgh, United Kingdom.; Jenkins RG; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Maher TM; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Keck Medicine of USC, University of Southern California, Los Angeles, California.; Molyneaux PL; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; Parfrey H; Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom.; Braybrooke R; Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom.; Blackwell TS; Vanderbilt University Medical Center, Nashville, Tennessee.; Jackson PD; Department of Pulmonary and Critical Care Medicine, Virginia Commonwealth University, Richmond, Virginia.; Nathan SD; Inova Fairfax Hospital, Falls Church, Virginia.; Porteous MK; Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.; Brown KK; National Jewish Health, Denver, Colorado.; Christie JD; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.; Collard HR; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California.; Eickelberg O; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.; Foster EE; Division of Pulmonary, Critical Care, and Sleep Medicine, School of Medicine, University of California, Davis, Sacramento, California.; Gibson KF; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.; Glassberg M; Division of Pulmonary, Critical Care and Sleep Medicine, College of Medicine, University of Arizona, Phoenix, Arizona.; Kass DJ; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.; Kropski JA; Vanderbilt University Medical Center, Nashville, Tennessee.; Lederer D; Regeneron Pharmaceuticals, Inc., Tarrytown, New York.; Linderholm AL; Department of Internal Medicine, University of California, Davis, Davis, California.; Loyd J; Vanderbilt University Medical Center, Nashville, Tennessee.; Mathai SK; Baylor University Medical Center, Dallas, Texas.; Montesi SB; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts.; Noth I; Department of Medicine.; Oldham JM; Department of Medicine and.; Palmisciano AJ; Division of Pulmonary, Critical Care and Sleep Medicine, Alpert Medical School, Brown University, Providence, Rhode Island.; Reichner CA; Division of Pulmonary, Critical Care and Sleep Medicine, MedStar Georgetown University Hospital, Washington, DC.; Rojas M; Division of Pulmonary, Critical Care, and Sleep Medicine, Ohio State University, Columbus, Ohio.; Roman J; Division of Pulmonary, Allergy, and Critical Care, Thomas Jefferson University, Philadelphia, Pennsylvania.; Schluger N; Columbia University Medical Center, New York, New York.; Shea BS; Division of Pulmonary, Critical Care and Sleep Medicine, Alpert Medical School, Brown University, Providence, Rhode Island.; Swigris JJ; National Jewish Health, Denver, Colorado.; Wolters PJ; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California.; Zhang Y; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.; Prele CMA; Institute for Respiratory Health, University of Western Australia, Perth, Australia.; Enghelmayer JI; Brown University, Providence, Rhode Island.; Hospital de Clínicas, Universidad de Buenos Aires, Buenos Aires, Argentina.; Otaola M; Instituto de Rehabilitación Psicofísica de Buenos Aires, Buenos Aires, Argentina.; Ryerson CJ; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.; Salinas M; Departamento de Medicina, Universidad de Chile, Santiago, Chile.; Sterclova M; Center for Rare Lung Diseases, Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark.; Gebremariam TH; College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.; Myllärniemi M; Department of Pulmonary Medicine, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland.; Carbone RG; Department of Internal Medicine, University of Genoa, Genoa, Italy.; Furusawa H; Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.; Hirose M; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan.; Inoue Y; National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan.; Miyazaki Y; Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.; Ohta K; National Hospital Organization Tokyo National Hospital, Tokyo, Japan.; Ohta S; Department of Medicine, Showa University, Tokyo, Japan.; Okamoto T; Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.; Kim DS; Asan Medical Center, University of Ulsan, Seoul, Republic of Korea.; Pardo A; Faculty of Sciences, Universidad Nacional Autónoma de México, Mexico City, Mexico.; Selman M; Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.; Aranda AU; Cardiopulmonary Research Center, Alliance Pulmonary Group, Guaynabo, Puerto Rico.; Park MS; Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.; Park JS; Seoul National University Bundang Hospital, Seoul National University, Seongnam, Republic of Korea.; Song JW; Asan Medical Center, University of Ulsan, Seoul, Republic of Korea.; Molina-Molina M; Respiratory Department and.; Planas-Cerezales L; Interstitial Lung Disease Multidisciplinary Unit, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain.; Westergren-Thorsson G; Department of Experimental Medical Science, Lung Biology Unit, Lund University, Lund, Sweden.; Smith AV; Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan.; Manichaikul AW; Center for Public Health Genomics, and.; Kim JS; Department of Medicine.; Rich SS; Center for Public Health Genomics, and.; Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.; Oelsner EC; Department of Medicine and Department of Epidemiology, Columbia University Medical Center, New York, New York.; Barr RG; Department of Medicine and Department of Epidemiology, Columbia University Medical Center, New York, New York.; Rotter JI; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, California.; Dupuis J; Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts.; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Quebec, Canada.; O'Connor G; Pulmonary Center, School of Medicine, Boston University, Boston, Massachusetts.; Vasan RS; Boston University and National Heart, Lung, and Blood Institute Framingham Heart Study, Boston, Massachusetts; and.; Cho MH; Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Silverman EK; Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Schwarz MI; Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.; Steele MP; Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.; Lee JS; Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.; Yang IV; Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.; Fingerlin TE; National Jewish Health, Denver, Colorado.; Schwartz DA; Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado. |
| Source: | American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2023 May 01; Vol. 207 (9), pp. 1194-1202. |
| Publication Type: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Thoracic Society Country of Publication: United States NLM ID: 9421642 Publication Model: Print Cited Medium: Internet ISSN: 1535-4970 (Electronic) Linking ISSN: 1073449X NLM ISO Abbreviation: Am J Respir Crit Care Med Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2000- : New York, NY : American Thoracic Society; Original Publication: New York, NY : American Lung Association, c1994- |
| MeSH Terms: | Idiopathic Pulmonary Fibrosis*/genetics; Humans ; Whole Genome Sequencing ; Exome |
| Abstract: | Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease. |
| Comments: | Comment in: Am J Respir Crit Care Med. 2023 May 1;207(9):1118-1120. doi: 10.1164/rccm.202301-0177ED.. (PMID: 36796091); Erratum in: Am J Respir Crit Care Med. 2024 Feb 15;209(4):462. doi: 10.1164/rccm.v209erratum2.. (PMID: 38358128) |
| References: | Am J Respir Crit Care Med. 2020 May 15;201(10):1240-1248. (PMID: 32011908); Chest. 2015 May;147(5):1361-1368. (PMID: 25539146); Am J Respir Crit Care Med. 2022 Jul 1;206(1):56-69. (PMID: 35417304); Lancet Respir Med. 2017 Nov;5(11):869-880. (PMID: 29066090); Thorax. 2004 Nov;59(11):977-80. (PMID: 15516475); BMJ Open Respir Res. 2014 Dec 10;1(1):e000057. (PMID: 25553246); Am J Hum Genet. 2009 Jan;84(1):52-9. (PMID: 19100526); Thorax. 2019 Dec;74(12):1131-1139. (PMID: 31558622); Genet Epidemiol. 2017 May;41(4):332-340. (PMID: 28318110); Commun Biol. 2021 Mar 23;4(1):392. (PMID: 33758299); N Engl J Med. 2007 Mar 29;356(13):1317-26. (PMID: 17392301); Nature. 2021 Feb;590(7845):290-299. (PMID: 33568819); Am J Respir Crit Care Med. 2019 Jul 15;200(2):175-183. (PMID: 30673508); Nat Genet. 2015 Oct;47(10):1114-20. (PMID: 26323059); Am J Respir Crit Care Med. 2010 Dec 1;182(11):1419-25. (PMID: 20656946); J Med Genet. 2008 Oct;45(10):654-6. (PMID: 18835860); Orphanet J Rare Dis. 2008 Mar 26;3:8. (PMID: 18366757); Nat Genet. 2013 Jun;45(6):613-20. (PMID: 23583980); Hum Hered. 2021 Feb 10;:1-13. (PMID: 33567433); Am J Respir Crit Care Med. 2015 Mar 15;191(6):646-55. (PMID: 25607374); Proc Natl Acad Sci U S A. 2007 May 1;104(18):7552-7. (PMID: 17460043); Am J Epidemiol. 2000 Aug 15;152(4):307-15. (PMID: 10968375); Nat Genet. 2015 May;47(5):512-7. (PMID: 25848748); J Med Genet. 2009 Jul;46(7):490-4. (PMID: 19443464); Respir Res. 2014 Apr 15;15:43. (PMID: 24730976); Am J Respir Cell Mol Biol. 2017 Jul;57(1):91-99. (PMID: 28272906); Am J Respir Crit Care Med. 2017 Jul 1;196(1):82-93. (PMID: 28099038); Am J Respir Crit Care Med. 2018 Sep 1;198(5):e44-e68. (PMID: 30168753); Am J Respir Crit Care Med. 2002 May 1;165(9):1322-8. (PMID: 11991887); Thorax. 2022 Aug;77(8):829-833. (PMID: 35688625); BMC Genet. 2016 Jun 07;17(1):74. (PMID: 27266705); Lancet Respir Med. 2013 Jun;1(4):309-317. (PMID: 24429156); Lancet Respir Med. 2018 Aug;6(8):603-614. (PMID: 29891356); N Engl J Med. 2018 Aug 23;379(8):797-798. (PMID: 30134133); Am J Hum Genet. 2012 Aug 10;91(2):224-37. (PMID: 22863193); N Engl J Med. 2001 Feb 22;344(8):573-9. (PMID: 11207353); N Engl J Med. 2011 Apr 21;364(16):1503-12. (PMID: 21506741); Eur Respir J. 2020 Dec 24;56(6):. (PMID: 32855221); Am J Respir Crit Care Med. 2019 Jul 15;200(2):199-208. (PMID: 31034279); Int J Occup Environ Health. 2008 Apr-Jun;14(2):117-23. (PMID: 18507288); Am J Respir Crit Care Med. 2023 Mar 1;207(5):587-593. (PMID: 36094461); Am J Respir Crit Care Med. 2020 Mar 1;201(5):564-574. (PMID: 31710517) |
| Grant Information: | U54 HG003067 United States HG NHGRI NIH HHS; R21 HL153700 United States HL NHLBI NIH HHS; R01 HL092577 United States HL NHLBI NIH HHS; I01 BX005295 United States BX BLRD VA; P30 DK063491 United States DK NIDDK NIH HHS; I01 BX002378 United States BX BLRD VA; 75N92020D00002 United States HL NHLBI NIH HHS; HHSN268201500003C United States HL NHLBI NIH HHS; P01 HL092870 United States HL NHLBI NIH HHS; N01 HC095161 United States HL NHLBI NIH HHS; 75N92020D00005 United States HL NHLBI NIH HHS; N01 HC095168 United States HL NHLBI NIH HHS; R01 HL120393 United States HL NHLBI NIH HHS; HHSN268201500001C United States HL NHLBI NIH HHS; UL1 TR001079 United States TR NCATS NIH HHS; N01 HC095169 United States HL NHLBI NIH HHS; R01 HL158668 United States HL NHLBI NIH HHS; 75N92020D00001 United States HL NHLBI NIH HHS; UH2 HL123442 United States HL NHLBI NIH HHS; U01 HL120393 United States HL NHLBI NIH HHS; U01 HL089897 United States HL NHLBI NIH HHS; R01 HL077612 United States HL NHLBI NIH HHS; UH3 HL151865 United States HL NHLBI NIH HHS; R01 HL145372 United States HL NHLBI NIH HHS; N01 HC095167 United States HL NHLBI NIH HHS; N01 HC095159 United States HL NHLBI NIH HHS; UH2/3-HL123442 United States HL NHLBI NIH HHS; 75N92020D00003 United States HL NHLBI NIH HHS; R01 HL093081 United States HL NHLBI NIH HHS; R01 HL105756 United States HL NHLBI NIH HHS; K23 HL150331 United States HL NHLBI NIH HHS; U01 HL089856 United States HL NHLBI NIH HHS; HHSN268201800001C United States HL NHLBI NIH HHS; N01 HC025195 United States HL NHLBI NIH HHS; P30 ES013508 United States ES NIEHS NIH HHS; HHSN268201500001I United States HL NHLBI NIH HHS; R21 HL129924 United States HL NHLBI NIH HHS; UL1 TR001420 United States TR NCATS NIH HHS; 75N92020D00004 United States HL NHLBI NIH HHS; N01 HC095163 United States HL NHLBI NIH HHS; 75N92020D00007 United States HL NHLBI NIH HHS; P01-HL0928701 United States HL NHLBI NIH HHS; HHSN268201500014C United States HL NHLBI NIH HHS; HHSN268201500003I United States HL NHLBI NIH HHS; UG3-HL151865 United States HL NHLBI NIH HHS; R01 HL146519 United States HL NHLBI NIH HHS; 75N92019D00031 United States HL NHLBI NIH HHS; UL1 TR000040 United States TR NCATS NIH HHS; N01 HC095166 United States HL NHLBI NIH HHS; UH3 HL123442 United States HL NHLBI NIH HHS; UG3 HL151865 United States HL NHLBI NIH HHS; 75N92020D00006 United States HL NHLBI NIH HHS; K23 HL130627 United States HL NHLBI NIH HHS; R01 HL117626 United States HL NHLBI NIH HHS; N01 HC095162 United States HL NHLBI NIH HHS; P01 HL162607 United States HL NHLBI NIH HHS; K23 HL138190 United States HL NHLBI NIH HHS; UL1 TR001881 United States TR NCATS NIH HHS; N01 HC095165 United States HL NHLBI NIH HHS; N01 HC095164 United States HL NHLBI NIH HHS; R01 HL149836 United States HL NHLBI NIH HHS; X01-HL134585 United States HL NHLBI NIH HHS; N01 HC095160 United States HL NHLBI NIH HHS |
| Contributed Indexing: | Keywords: TOPMed; genetic association studies; interstitial lung disease; telomerase; whole-genome sequencing |
| Entry Date(s): | Date Created: 20230105 Date Completed: 20230503 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10161752 |
| DOI: | 10.1164/rccm.202207-1331OC |
| PMID: | 36602845 |
| Database: | MEDLINE |
Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't