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Am J Respir Crit Care Med. 2019 Apr 29. doi: 10.1164/rccm.201810-1891OC. [Epub ahead of print]

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

Moore C1, Blumhagen RZ2, Yang IV3, Walts A4, Powers J5, Walker T6, Bishop M6, Russell P7, Vestal B2, Cardwell J6, Markin CR8, Mathai SK9, Schwarz MI10, Steele MP11, Lee J12, Brown KK2, Loyd JE13, Crapo JD14, Silverman EK15, Cho MH16, James JA17, Guthridge JM17, Cogan JD18, Kropski JA8, Swigris JJ19, Bair C2, Soon Kim D20, Ji W21, Kim H21, Song JW22, Maier LA2, Pacheco KA2, Hirani N23, Poon AS24, Li F24, Jenkins RG25, Braybrooke R26, Saini G27, Maher TM28, Molyneaux PL29, Saunders P28, Zhang Y30, Gibson KF31, Kass DJ32, Rojas M33, Sembrat J34, Wolters PJ35, Collard HR36, Sundy JS37, O'Riordan T38, Strek ME39, Noth I40, Ma SF41, Porteous MK42, Kreider ME43, Patel NB44, Inoue Y45, Hirose M46, Arai T47, Akagawa S48, Eickelberg O6, Fernandez IE49, Behr J50, Mogulkoc N51, Corte TJ52,53, Glaspole I54,55, Tomassetti S56, Ravaglia C57, Poletti V58, Crestani B59, Borie R60, Kannengiesser C61, Parfrey H62, Fiddler C63, Rassl D64, Molina-Molina M65, Machahua C66,67, Montes Worboys A68, Gudmundsson G69, Isaksson HJ70, Lederer DJ71, Podolanczuk AJ72, Montesi SB73, Bendstrup E74, Danchel V75, Selman M76, Pardo A77, Henry MT78, Keane MP79, Doran P80, Vašáková M81, Sterclova M82, Ryerson CJ83, Wilcox PG84, Okamoto T85, Furusawa H86, Miyazaki Y87, Laurent G88, Baltic S89, Prele C90,91, Moodley Y92, Shea BS93,94, Ohta K95, Suzukawa M96, Narumoto O97, Nathan SD98, Venuto DC99, Woldehanna ML99, Kokturk N100, de Andrade JA101, Luckhardt T102, Kulkarni T103, Bonella F104, Donnelly SC105, McElroy A106, Armstrong ME106, Aranda A107, Carbone RG108, Puppo F108, Beckman KB109, Nickerson DA110, Fingerlin TE111, Schwartz DA112.

Author information

1
National Jewish Health, 2930, Division of Biostatistics and Bioinformatics, Denver, Colorado, United States.
2
National Jewish Health, 2930, Denver, Colorado, United States.
3
National Jewish Health, Medicine, Denver, Colorado, United States.
4
University of Colorado, Department of Medicine, Denver, Colorado, United States.
5
University of Colorado School of Medicine, Medicine, Aurora, Colorado, United States.
6
University of Colorado Denver School of Medicine, 12225, Medicine, Aurora, Colorado, United States.
7
University of Colorado, Denver, Department of Medicine, Denver, Colorado, United States.
8
Vanderbilt University Medical Center, 12328, Medicine, Nashville, Tennessee, United States.
9
Baylor Scott and White Health, 423342, Dallas, Texas, United States.
10
University of Colorado, Pulmonary and Critical Care Medicine, Denver, Colorado, United States.
11
University of Colorado, Denver School of Medicine, Medicine, Aurora, Colorado, United States.
12
University of Colorado Denver, Aurora, Colorado, United States.
13
Vanderbilt Univ Medical Center, Nashville, Tennessee, United States.
14
National Jewish Medical & Research Ctr., Denver, Colorado, United States.
15
Brigham and Women's Hospital, 1861, Channing Division of Network Medicine, Boston, Massachusetts, United States.
16
Harvard Medical School, Channing Division of Respiratory Medicine, Boston, Massachusetts, United States.
17
Oklahoma Medical Research Foundation, 6190, Oklahoma City, Oklahoma, United States.
18
Vanderbilt University School of Medicine, Pediatrics, Nashville, Tennessee, United States.
19
National Jewish Health, 2930, Medicine, Denver, Colorado, United States.
20
Asan Medical Center, 65526, Songpa-gu, Seoul, Korea (the Republic of).
21
Asan Medical Center, Dept of Respiratory Medicine and Critical Care, Seoul, Korea, Republic of.
22
University of Ulsan College of Medicine, Asan Medical Center, Pulmonary and Critical Care Medicine, Seoul, Korea (the Republic of).
23
University of Nottingham, Edinburgh, United Kingdom of Great Britain and Northern Ireland.
24
University of Edinburgh MRC Centre for Inflammation Research, 47954, Edinburgh, United Kingdom of Great Britain and Northern Ireland.
25
University of Nottingham, Nottingham, United Kingdom of Great Britain and Northern Ireland.
26
University of Nottingham , Respiratory Medicine, Nottingham , United Kingdom of Great Britain and Northern Ireland.
27
University of Nottingham, 6123, Nottingham, Nottinghamshire, United Kingdom of Great Britain and Northern Ireland.
28
Royal Brompton and Harefield NHS Foundation Trust, 4964, London, United Kingdom of Great Britain and Northern Ireland.
29
Imperial College London, National Heart and Lung Institute, London, United Kingdom of Great Britain and Northern Ireland.
30
University of Pittsburgh, Medicine, Pittsburgh, Pennsylvania, United States.
31
University of Pittsburgh School of Medicine, Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Pittsburgh, Pennsylvania, United States.
32
University of Pittsburgh and the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Medicine, Pittsburgh, Pennsylvania, United States.
33
University of Pittsburgh, Department of Medicine, Pittsburgh, Pennsylvania, United States.
34
University of Pittsburgh, 6614, Simmons Center for Interstitial Lung Disease, Pittsburgh, Pennsylvania, United States.
35
University of California, Medicine/CVRI, San Francisco, California, United States.
36
University of Colorado San Francisco, Medicine, San Francisco, California, United States.
37
Gilead Sciences, Inc., Foster City, California, United States.
38
Gilead Sciences Inc, Medical Research, Seattle, Washington, United States.
39
University of Chicago Hosp, Department of Medicine, Chicago, Illinois, United States.
40
University of Virginia, Division of Pulmonary & Critical Care & Sleep Medicine, Department of Medicine, , Charlottesville, Virginia, United States.
41
University of Virginia, 2358, Charlottesville, Virginia, United States.
42
Hospital of the University of Pennsylvania, Pulmonary, Allergy, and Critical Care, Philadelphia, Pennsylvania, United States.
43
University of Pennsylvania Perelman School of Medicine, 14640, Philadelphia, Pennsylvania, United States.
44
Temple University, Internal Medicine, Philadelphia, Pennsylvania, United States.
45
National Hospital Organization Kinki-Chuo Chest Medical Center, Clinical Resaerch Center, Osaka, Japan.
46
National Hospital Organization Osaka National Hospital, 13707, Osaka, Japan.
47
National Hospital Organization Kinki-chuo Chest Medical Center, Department of Diffuse Lung Diseases and Respiratory Failure, Clinical Research Center, Sakai, Osaka, Japan.
48
National Hospital Organization Tokyo, Tokyo, Japan.
49
Helmholtz Zentrum Muenchen, Comprehensive Pneumology Center, Munich, Bayern, Germany.
50
University Hospital Munich, Munich, Germany.
51
Ege University Hospital, Department of Pulmonology, Bornova, Izmir, Turkey.
52
Royal Prince Alfred Hospital, Department of Respiratory Medicine, Sydney, New South Wales, Australia.
53
University of Sydney, 4334, Medical School, Sydney, New South Wales, Australia.
54
Alfred Health , Allergy, Immunology & Respiratory Medicine Department, Melbourne, Victoria, Australia.
55
Monash University, Central Clinical School, Department of Medicine, Melbourne, Victoria, Australia.
56
GB Morgagni Hospital, Diseases of the Thorax, Forlì, Italy.
57
Morgagni Pierantoni Hospital, Pulmonology, Forlì, Italy.
58
GB MORGAGNI HOSPITAL, INTERVENTIONAL PNEUMOLOGY, FORLì, FC, Italy.
59
Hopital Bichat, Paris, France.
60
Universite Paris Diderot, 27066, Paris, Île-de-France, France.
61
Assistance Publique Hôpitaux de Paris, Hôpital Bichat; Université Paris Diderot, Sorbonne Paris Cité, Service de génétique, Paris, France.
62
Cambridge Regional Interstitial Lung Disease Service, Papworth and Addenbrooke\'s Hospitals, Cambridge, United Kingdom of Great Britain and Northern Ireland.
63
Royal Papworth Hospital and Cambridge University Hospitals, Cambridge, United Kingdom of Great Britain and Northern Ireland.
64
Papworth Hospital, Pathology, Cambridge, United Kingdom of Great Britain and Northern Ireland.
65
Pneumology, ILD Unit. University Hospital of Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
66
Institut d'Investigacio Biomedica de Bellvitge, 115336, Pneumology Research Group, Barcelona, Spain.
67
CIBERES, Barcelona, Barcelona, Spain.
68
University of Florida, Medicine, Gainesville, Florida, United States.
69
Landspitali University Hospital, 37557, Respiratory Medicine, Reykjavik, United States.
70
Landspitali University Hospital, Pathology, Reykjavik, Iceland.
71
Columbia University, Divison of Pulmonary, Allergy, and Critical Care Medicine, New York, New York, United States.
72
Columbia University, 5798, New York, New York, United States.
73
Massachusetts General Hospital, 2348, Boston, Massachusetts, United States.
74
Aarhus Universitetshospital, 11297, Aarhus, Denmark.
75
Aarhus Universitet, 1006, Aarhus, Denmark.
76
Instituto Nacional de Enfermedades Respiratorias, Mexico DF, Mexico.
77
Universidad Nacional Autónoma de México, Facultad de Ciencias, México DF, Mexico.
78
Cork University Hospital, Department of Respiratory Medicine, Cork, Ireland.
79
University College Dublin, 8797, Dublin, Ireland.
80
St Vincent's University Hospital, Dublin, Ireland.
81
Fakultni Thomayerova nemocnice s poliklinikou, 48209, Department of Respiratory Medicine, Praha, Czech Republic.
82
University Thomayer's Hospital, Prague, Department of Respiratory Medicine, Prague, Czech Republic.
83
University of British Columbia, Medicine, Vancouver, British Columbia, Canada.
84
St Paul's Hospital, Vancouver, British Columbia, Canada.
85
UC Denver, Anschutz Medical Campus, Medicine, Aurora, Colorado, United States.
86
University of Colorado at Denver - Anschutz Medical Campus, 129263, Aurora, Colorado, United States.
87
Tokyo Medical and Dental University, Respiratory Medicine, Tokyo, Japan.
88
University College London Medical School, Centre for Respiratory Research, London, United Kingdom of Great Britain and Northern Ireland.
89
Institute for Respiratory Health, Molecular Genetics and Inflammation Unit, Perth, Western Australia, Australia.
90
Lung Institute of Western Australia, Centre for Asthma Allergy and Respiratory Research, Perth, Western Australia, Australia.
91
Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, Perth, Western Australia, Australia.
92
The University of Western Australia, Respiratory Medicine, Perth, Western Australia, Australia.
93
Massachusetts General Hospital, Pulmonary and Critical Care Unit, Boston, Massachusetts, United States.
94
Massachusetts General Hospital, Center for Immunology and Inflammatory Diseases, Charlestown, Massachusetts, United States.
95
National Hospital Organization Tokyo National Hospita, direcror, Tokyo, Japan.
96
National Hospital Organization, Tokyo National Hospital, Tokyo, Japan.
97
Tokyo National Hospital, Tokyo, Japan.
98
Inova Transplant Center, Inova Fairfax Hospital, Falls Church, Virginia, United States.
99
Inova Fairfax Hospital, 23146, Falls Church, Virginia, United States.
100
Gazi Universitesi, 37511, Ankara, Ankara, Turkey.
101
University of Alabama at Birmingham, Medicine, Div of Pulmonary, Allergy, and Critical Care, Birmingham, Alabama, United States.
102
University of Alabama at Birmingham, 9968, Birmingham, Alabama, United States.
103
University of Alabama at Birmingham, Pulmonary, Allergy and Critical Care, Birmingham, Alabama, United States.
104
Universitat Duisburg-Essen, 27170, Duisburg, Nordrhein-Westfalen, Germany.
105
University of Dublin Trinity College, 8809, Medicine, Dublin, Ireland.
106
Trinity College, Dublin, Ireland.
107
CardioPulmonary Research Center at Alliance Pulmonary Group, Guaynabo, Puerto Rico.
108
University of Genoa, Genoa, Italy.
109
University of Minnesota System, 311816, Minneapolis, Minnesota, United States.
110
University of Washington, Department of Genome Sciences, Seattle, Washington, United States.
111
National Jewish Health, Denver, United States ; fingerlint@njhealth.org.
112
University of Colorado, School of Medicine, Department of Medicine, Aurora, Colorado, United States.

Abstract

RATIONALE:

Several common and rare genetic variants have been associated with Idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung.

OBJECTIVE:

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 controls (N=4,442) across genes and regions previously associated with disease. We tested for association between disease and a) individual common variants via logistic regression and b) groups of rare variants via a sequence kernel association test.

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 OR of 5.45 (95% CI: 4.91-6.06) for one copy of the risk allele and 18.68 (95% CI: 13.34-26.17) for two copies of the risk allele (p=9.60 x 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 risk of IPF in the TERT and RTEL1 gene regions, 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; these genetic variants focus on biological mechanisms of host defense and cell senescence.

KEYWORDS:

DNA Sequence Analysis

PMID:
31034279
DOI:
10.1164/rccm.201810-1891OC
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