Article open access publication

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

American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, ISSN 1535-4970

Volume 200, 2, 2019

DOI:10.1164/rccm.201810-1891oc, Dimensions: pub.1113814828, PMC: PMC6635791, PMID: 31034279,

Authors

Moore, Camille (1) (2)
Crapo, James D. (2) (3)
Maier, Lisa A. (1) (2) (3)
Hirani, Nikhil (8) (9)
Li, Feng (9)
Noth, Imre (16)
Arai, Toru (18)
Keane, Michael P. (36) (37)
Doran, Peter (36) (37)
Okamoto, Tsukasa (3) (40)
Laurent, Geoffrey (41) (42)
Prele, Cecilia (41) (42)
Ohta, Ken (19)
Fingerlin, Tasha E. (1) (2) (3)
Schwartz, David A. (2) (3) (53)

Affiliations

Organisations

  1. (1) School of Public Health
  2. (2) National Jewish Health, grid.240341.0
  3. (3) Department of Medicine, and
  4. (4) Vanderbilt University, grid.152326.1
  5. (5) Brigham and Women’s Hospital, Harvard School of Medicine, Boston, Massachusetts
  6. (6) Oklahoma Medical Research Foundation, grid.274264.1
  7. (7) Asan Medical Center, grid.413967.e
  8. (8) Edinburgh Royal Infirmary, grid.418716.d
  9. (9) University of Edinburgh, grid.4305.2
  10. (10) University of Nottingham, grid.4563.4
  11. (11) Royal Brompton Hospital, grid.439338.6
  12. (12) University of Pittsburgh, grid.21925.3d
  13. (13) University of California, San Francisco, grid.266102.1
  14. (14) Gilead Sciences (United States), grid.418227.a
  15. (15) University of Chicago, grid.170205.1
  16. (16) University of Virginia, grid.27755.32
  17. (17) University of Pennsylvania, grid.25879.31
  18. (18) National Kinki Chuo Hospital for Chest Disease, grid.415611.6
  19. (19) Tokyo National Hospital, grid.417136.6
  20. (20) Helmholtz Zentrum München, grid.4567.0
  21. (21) Klinikum der Universität München, grid.411095.8
  22. (22) Ege Üniversitesi Tıp Fakültesi Hastanesi, grid.412190.f
  23. (23) Royal Prince Alfred Hospital, grid.413249.9
  24. (24) The Alfred Hospital, grid.1623.6
  25. (25) Ospedale G.B. Morgagni - L.Pierantoni, grid.415079.e
  26. (26) Paris Diderot University, grid.7452.4
  27. (27) Cambridge University Hospitals NHS Foundation Trust, grid.24029.3d
  28. (28) Respiratory Department, University Hospital of Bellvitge, University of Barcelona, Barcelona, Spain
  29. (29) National University Hospital of Iceland, University of Iceland, Reykjavik, Iceland
  30. (30) Columbia University, grid.21729.3f
  31. (31) Massachusetts General Hospital, grid.32224.35
  32. (32) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  33. (33) Instituto Nacional de Enfermedades Respiratorias, grid.419179.3
  34. (34) National Autonomous University of Mexico, grid.9486.3
  35. (35) Cork University Hospital, grid.411916.a
  36. (36) St. Vincent's University Hospital, grid.412751.4
  37. (37) University College Dublin, grid.7886.1
  38. (38) Thomayerova nemocnice, grid.448223.b
  39. (39) University of British Columbia, grid.17091.3e
  40. (40) Tokyo Medical and Dental University, grid.265073.5
  41. (41) University of Western Australia, grid.1012.2
  42. (42) Institute for Respiratory Health and
  43. (43) Brown University, grid.40263.33
  44. (44) Inova Fairfax Hospital, grid.417781.c
  45. (45) Gazi University, grid.25769.3f
  46. (46) University of Alabama at Birmingham, grid.265892.2
  47. (47) University of Duisburg-Essen, grid.5718.b
  48. (48) Trinity College Dublin, grid.8217.c
  49. (49) CardioPulmonary Reserach Center, Alliance Pulmonary Group, Guaynabo, Puerto Rico
  50. (50) University of Genoa, grid.5606.5
  51. (51) University of Minnesota, grid.17635.36
  52. (52) University of Washington, grid.34477.33
  53. (53) University of Colorado Denver, grid.241116.1

Description

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 × 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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