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Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants
AL. Peljto, RZ. Blumhagen, AD. Walts, J. Cardwell, J. Powers, TJ. Corte, JL. Dickinson, I. Glaspole, YP. Moodley, MK. Vasakova, E. Bendstrup, JR. Davidsen, R. Borie, B. Crestani, P. Dieude, F. Bonella, U. Costabel, G. Gudmundsson, SC. Donnelly,...
Language English Country United States
Document 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
Grant support
R01 HL158668
NHLBI NIH HHS - United States
UH3 HL151865
NHLBI NIH HHS - United States
R01 HL145372
NHLBI NIH HHS - United States
UH2/3-HL123442
NHLBI NIH HHS - United States
K23 HL150331
NHLBI NIH HHS - United States
P01-HL0928701
NHLBI NIH HHS - United States
UG3-HL151865
NHLBI NIH HHS - United States
R01 HL149836
NHLBI NIH HHS - United States
X01-HL134585
NHLBI NIH HHS - United States
NLK
Free Medical Journals
from 1997-07-01 to 1 year ago
Freely Accessible Science Journals
from 1997 to 1 year ago
Open Access Digital Library
from 1998-01-01
- MeSH
- Exome MeSH
- Idiopathic Pulmonary Fibrosis * genetics MeSH
- Humans MeSH
- Whole Genome Sequencing MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
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.
Allergy Asthma and Clinical Immunology Clinic Alfred Health Sydney Australia
Asan Medical Center University of Ulsan Seoul Republic of Korea
Baylor University Medical Center Dallas Texas
Brown University Providence Rhode Island
Cardiopulmonary Research Center Alliance Pulmonary Group Guaynabo Puerto Rico
Center for Public Health Genomics and
College of Health Sciences Addis Ababa University Addis Ababa Ethiopia
Columbia University Medical Center New York New York
Departamento de Medicina Universidad de Chile Santiago Chile
Department of Biostatistics School of Public Health Boston University Boston Massachusetts
Department of Biostatistics School of Public Health University of Michigan Ann Arbor Michigan
Department of Clinical Medicine Aarhus University Aarhus Denmark
Department of Diseases of the Thorax G B Morgagni Hospital Forlì Italy
Department of Experimental Medical Science Lung Biology Unit Lund University Lund Sweden
Department of Internal Medicine University of California Davis Davis California
Department of Internal Medicine University of Genoa Genoa Italy
Department of Medical and Surgical Sciences DIMES University of Bologna Bologna Italy
Department of Medicine Showa University Tokyo Japan
Department of Medicine University of British Columbia Vancouver British Columbia Canada
Department of Medicine University of Colorado Anschutz Medical Campus Aurora Colorado
Department of Public Health Sciences University of Virginia Charlottesville Virginia
Department of Pulmonary Medicine Heart and Lung Center Helsinki University Hospital Helsinki Finland
Department of Pulmonology Ege University Hospital Izmir Turkey
Department of Respiratory Medicine and Sleep Landspitali University Hospital Reykjavik Iceland
Department of Respiratory Medicine Cork University Hospital Cork Ireland
Department of Respiratory Medicine Tokyo Medical and Dental University Tokyo Japan
Department of Respiratory Medicine University of Western Australia Perth Australia
Department of Respiratory Medicine University Thomayer Hospital Prague Czech Republic
Division of Pulmonary and Critical Care Medicine Massachusetts General Hospital Boston Massachusetts
Division of Pulmonary Critical Care and Sleep Medicine Ohio State University Columbus Ohio
Division of Respiratory Medicine University of Nottingham Nottingham United Kingdom
Faculty of Medicine Gazi University Ankara Turkey
Faculty of Medicine University of Iceland Reykjavik Iceland
Faculty of Sciences Universidad Nacional Autónoma de México Mexico City Mexico
Fondazione Policlinico A Gemelli IRCCS Rome Italy
Hospital de Clínicas Universidad de Buenos Aires Buenos Aires Argentina
Hospital of the University of Pennsylvania Philadelphia Pennsylvania
Inova Fairfax Hospital Falls Church Virginia
Institute for Respiratory Health University of Western Australia Perth Australia
Instituto de Rehabilitación Psicofísica de Buenos Aires Buenos Aires Argentina
Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas Mexico City Mexico
Interventional Pulmonology Unit Careggi University Hospital Florence Italy
Keck Medicine of USC University of Southern California Los Angeles California
Mater Misericordiae University Hospital Dublin Ireland
Menzies Institute of Medical Research University of Tasmania Hobart Tasmania Australia
National Heart and Lung Institute Imperial College London London 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 Lung Transplantation Centre Mater Misericordiae University Hospital Dublin Ireland
Perelman School of Medicine University of Pennsylvania Philadelphia Pennsylvania
Pulmonary Center School of Medicine Boston University Boston Massachusetts
Regeneron Pharmaceuticals Inc Tarrytown New York
Royal Papworth Hospital NHS Foundation Trust Cambridge United Kingdom
Royal Prince Alfred Hospital University of Sydney Sydney Australia
Seoul National University Bundang Hospital Seoul National University Seongnam Republic of Korea
Service de Rhumatologie Hopital Bichat Paris France
Severance Hospital Yonsei University College of Medicine Seoul Republic of Korea
St Vincent's University Hospital University College Dublin Dublin Ireland
Trinity College Dublin Dublin Ireland
Università Cattolica del Sacro Cuore Rome Italy
References provided by Crossref.org
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- $a 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.
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- $a X01-HL134585 $p NHLBI NIH HHS $2 United States
- LZP __
- $a Pubmed-20230718
