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Moore, C.* ; Blumhagen, R.Z.* ; Yang, I.V.* ; Walts, A.* ; Powers, J.* ; Walker, T.* ; Bishop, M.* ; Russell, P.* ; Vestal, B.* ; Cardwell, J.* ; Markin, C.R.* ; Mathai, S.K.* ; Schwarz, M.I.* ; Steele, M.P.* ; Lee, J.* ; Brown, K.K.* ; Loyd, J.E.* ; Crapo, J.D.* ; Silverman, E.K.* ; Cho, M.H.* ; James, J.A.* ; Guthridge, J.M.* ; Cogan, J.D.* ; Kropski, J.A.* ; Swigris, J.J.* ; Bair, C.* ; Soon Kim, D.* ; Ji, W.* ; Kim, H.* ; Song, W.J.* ; Maier, L.A.* ; Pacheco, K.A.* ; Hirani, N.* ; Poon, A.S.* ; Li, F.* ; Jenkins, R.G.* ; Braybrooke, R.* ; Saini, G.* ; Maher, T.M.* ; Molyneaux, P.L.* ; Saunders, P.* ; Zhang, Y.* ; Gibson, K.F.* ; Kass, D.J.* ; Rojas, M.* ; Sembrat, J.* ; Wolters, P.J.* ; Collard, H.R.* ; Sundy, J.S.* ; O'Riordan, T.* ; Strek, M.E.* ; Noth, I.* ; Ma, S.F.* ; Porteous, M.K.* ; Kreider, M.E.* ; Patel, N.B.* ; Inoue, Y.* ; Hirose, M.* ; Arai, T.* ; Akagawa, S.* ; Eickelberg, O. ; Fernandez, I.E. ; Behr, J.* ; Mogulkoc, N.* ; Corte, T.J.* ; Glaspole, I.* ; Tomassetti, S.* ; Ravaglia, C.* ; Poletti, V.* ; Crestani, B.* ; Borie, R.* ; Kannengiesser, C.* ; Parfrey, H.* ; Fiddler, C.* ; Rassl, D.* ; Molina-Molina, M.* ; Machahua, C.* ; Montes Worboys, A.* ; Gudmundsson, G.* ; Isaksson, H.J.* ; Lederer, D.J.* ; Podolanczuk, A.J.* ; Montesi, S.B.* ; Bendstrup, E.* ; Danchel, V.* ; Selman, M.* ; Pardo, A.* ; Henry, M.T.* ; Keane, M.P.* ; Doran, P.* ; Vašáková, M.* ; Sterclova, M.* ; Ryerson, C.J.* ; Wilcox, P.G.* ; Okamoto, T.* ; Furusawa, H.* ; Miyazaki, Y.* ; Laurent, G.* ; Baltic, S.* ; Prele, C.* ; Moodley, Y.* ; Shea, B.S.* ; Ohta, K.* ; Suzukawa, M.* ; Narumoto, O.* ; Nathan, S.D.* ; Venuto, D.C.* ; Woldehanna, M.L.* ; Kokturk, N.* ; de Andrade, J.A.* ; Luckhardt, T.* ; Kulkarni, T.* ; Bonella, F.* ; Donnelly, S.C.* ; McElroy, A.* ; Armstrong, M.E.* ; Aranda, A.* ; Carbone, R.G.* ; Puppo, F.* ; Beckman, K.B.* ; Nickerson, D.A.* ; Fingerlin, T.E.* ; Schwartz, D.A.*

Resequencing study confirms host defense and cell senescence gene variants contribute to the risk of idiopathic pulmonary fibrosis.

Am. J. Respir. Crit. Care Med. 200, 199-208 (2019)
Verlagsversion Postprint DOI PMC
Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Targeted Resequencing ; Idiopathic Pulmonary Fibrosis ; Genetic Variants ; Rare Variants ; Disease Risk Alleles; Muc5b Promoter Polymorphism; Genome; Susceptibility; Mutations; Association; Expression; Disease; Loci
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Zeitschrift American Journal of Respiratory and Critical Care Medicine
Quellenangaben Band: 200, Heft: 2, Seiten: 199-208 Artikelnummer: , Supplement: ,
Verlag American Thoracic Society
Verlagsort 25 Broadway, 18 Fl, New York, Ny 10004 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)