Elisabeth Bendstrup

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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  • Isis Enlil Fernandez, HMGU Helmholtz Zentrum Munchen, Helmholtz Association, Helmholtz-Center Munich - German Research Center for Environmental Health, Inst Epidemiol 2, German Res Ctr Environm Hlth, Inst Epidemiol 2
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  • Caroline Kannengiesser, Univ Paris Diderot, Sorbonne Universite, Pierre & Marie Curie University - Paris VI, University of Paris Diderot - Paris VII, Universite Sorbonne Paris Cite-USPC (ComUE), Assistance Publique Hopitaux Paris (APHP), Hopital Universitaire Bichat-Claude Bernard - APHP, Serv Pneumol A, Hop Bichat, AP HP
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  • Helen Parfrey, Cambridge Univ Hosp NHS Fdn Trust, University of Cambridge, Addenbrookes Hosp, Dept Radiol
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  • Christine Fiddler, Cambridge Univ Hosp NHS Fdn Trust, University of Cambridge, Addenbrookes Hosp, Dept Radiol
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  • Doris Rassl, Cambridge Univ Hosp NHS Fdn Trust, University of Cambridge, Addenbrookes Hosp, Dept Radiol
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  • Maria Molina-Molina, Univ Barcelona, Catalan Health Institute, Bellvitge University Hospital, University of Barcelona, Univ Hosp Bellvitge, Resp Dept
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  • Carlos Machahua, Univ Barcelona, Catalan Health Institute, Bellvitge University Hospital, University of Barcelona, Univ Hosp Bellvitge, Resp Dept
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  • Ana Montes Worboys, Univ Barcelona, Catalan Health Institute, Bellvitge University Hospital, University of Barcelona, Univ Hosp Bellvitge, Resp Dept
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  • Gunnar Gudmundsson, Univ Iceland, Landspitali National University Hospital, University of Iceland, Natl Univ Hosp Iceland
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  • Helgi J. Isaksson, Univ Iceland, Landspitali National University Hospital, University of Iceland, Natl Univ Hosp Iceland
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  • David J. Lederer, Columbia Univ, Columbia University, NewYork-Presbyterian Hospital, Dept Med, Irving Med Ctr
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  • Elisabeth Bendstrup
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  • Moises Selman, Inst Nacl Enfermedades Resp Ismael Cosio Villegas
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  • Joao A. de Andrade, Univ Alabama Birmingham, University of Alabama System, University of Alabama Birmingham, Dept Med
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  • Tracy Luckhardt, Univ Alabama Birmingham, University of Alabama System, University of Alabama Birmingham, Dept Med
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  • Tejaswini Kulkarni, Univ Alabama Birmingham, University of Alabama System, University of Alabama Birmingham, Dept Med
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  • Francesco Bonella, Univ Duisburg Essen, University of Duisburg Essen, Univ Hosp, Ruhrlandklin
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  • Seamus C. Donnelly, Tallaght Univ Hosp, Trinity College Dublin, Trinity Coll Dublin, Dept Med
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  • Aoife McElroy, Tallaght Univ Hosp, Trinity College Dublin, Trinity Coll Dublin, Dept Med
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  • Michelle E. Armstong, Tallaght Univ Hosp, Trinity College Dublin, Trinity Coll Dublin, Dept Med
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  • Alvaro Aranda, CardioPulm Reserach Ctr, Alliance Pulm Grp
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  • Roberto G. Carbone, Univ Genoa, University of Genoa, Dept Internal Med
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  • Francesco Puppo, Univ Genoa, University of Genoa, Dept Internal Med
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  • Kenneth B. Beckman, Univ Minnesota, University of Minnesota System, University of Minnesota Twin Cities, Biomed Genom Ctr
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  • Deborah A. Nickerson, Univ Washington, University of Washington, University of Washington Seattle, Northwest Genom Ctr
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  • Tasha E. Fingerlin, Univ Colorado, University of Colorado System, University of Colorado Denver, University of Colorado Health Science Center, Dept Med
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  • David A. Schwartz, Univ Colorado, University of Colorado System, University of Colorado Denver, Dept Immunol

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 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 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.

Original languageEnglish
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume200
Issue2
Pages (from-to)199-208
Number of pages10
ISSN1073-449X
DOIs
Publication statusPublished - 15 Jul 2019

    Research areas

  • targeted resequencing, idiopathic pulmonary fibrosis, genetic variants, rare variants, disease risk alleles, MUC5B PROMOTER POLYMORPHISM, GENOME, SUSCEPTIBILITY, MUTATIONS, ASSOCIATION, EXPRESSION, DISEASE, LOCI

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ID: 162445831