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

Publication ,  Journal Article
Moore, C; Blumhagen, RZ; Yang, IV; Walts, A; Powers, J; Walker, T; Bishop, M; Russell, P; Vestal, B; Cardwell, J; Markin, CR; Mathai, SK ...
Published in: Am J Respir Crit Care Med
July 15, 2019

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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Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

July 15, 2019

Volume

200

Issue

2

Start / End Page

199 / 208

Location

United States

Related Subject Headings

  • Telomere-Binding Proteins
  • Telomerase
  • Sequence Analysis, DNA
  • Respiratory System
  • RNA
  • Pulmonary Surfactant-Associated Protein C
  • Pulmonary Surfactant-Associated Protein A
  • Promoter Regions, Genetic
  • Mucin-5B
  • Male
 

Citation

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Chicago
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MLA
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Moore, C., Blumhagen, R. Z., Yang, I. V., Walts, A., Powers, J., Walker, T., … Schwartz, D. A. (2019). Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med, 200(2), 199–208. https://doi.org/10.1164/rccm.201810-1891OC
Moore, Camille, Rachel Z. Blumhagen, Ivana V. Yang, Avram Walts, Julie Powers, Tarik Walker, Makenna Bishop, et al. “Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.Am J Respir Crit Care Med 200, no. 2 (July 15, 2019): 199–208. https://doi.org/10.1164/rccm.201810-1891OC.
Moore C, Blumhagen RZ, Yang IV, Walts A, Powers J, Walker T, et al. Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2019 Jul 15;200(2):199–208.
Moore, Camille, et al. “Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.Am J Respir Crit Care Med, vol. 200, no. 2, July 2019, pp. 199–208. Pubmed, doi:10.1164/rccm.201810-1891OC.
Moore C, Blumhagen RZ, Yang IV, Walts A, Powers J, Walker T, Bishop M, Russell P, Vestal B, Cardwell J, Markin CR, Mathai SK, Schwarz MI, Steele MP, Lee J, Brown KK, Loyd JE, Crapo JD, Silverman EK, Cho MH, James JA, Guthridge JM, Cogan JD, Kropski JA, Swigris JJ, Bair C, Kim DS, Ji W, Kim H, Song JW, Maier LA, Pacheco KA, Hirani N, Poon AS, Li F, Jenkins RG, Braybrooke R, Saini G, Maher TM, Molyneaux PL, Saunders P, Zhang Y, Gibson KF, Kass DJ, Rojas M, Sembrat J, Wolters PJ, Collard HR, Sundy JS, O’Riordan T, Strek ME, Noth I, Ma S-F, Porteous MK, Kreider ME, Patel NB, Inoue Y, Hirose M, Arai T, Akagawa S, Eickelberg O, Fernandez IE, Behr J, Mogulkoc N, Corte TJ, 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, Worboys AM, Gudmundsson G, Isaksson HJ, Lederer DJ, Podolanczuk AJ, Montesi SB, Bendstrup E, Danchel V, Selman M, Pardo A, Henry MT, Keane MP, Doran P, Vašáková M, Sterclova M, Ryerson CJ, Wilcox PG, Okamoto T, Furusawa H, Miyazaki Y, Laurent G, Baltic S, Prele C, Moodley Y, Shea BS, Ohta K, Suzukawa M, Narumoto O, Nathan SD, Venuto DC, Woldehanna ML, Kokturk N, de Andrade JA, Luckhardt T, Kulkarni T, Bonella F, Donnelly SC, McElroy A, Armstong ME, Aranda A, Carbone RG, Puppo F, Beckman KB, Nickerson DA, Fingerlin TE, Schwartz DA. Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2019 Jul 15;200(2):199–208.

Published In

Am J Respir Crit Care Med

DOI

EISSN

1535-4970

Publication Date

July 15, 2019

Volume

200

Issue

2

Start / End Page

199 / 208

Location

United States

Related Subject Headings

  • Telomere-Binding Proteins
  • Telomerase
  • Sequence Analysis, DNA
  • Respiratory System
  • RNA
  • Pulmonary Surfactant-Associated Protein C
  • Pulmonary Surfactant-Associated Protein A
  • Promoter Regions, Genetic
  • Mucin-5B
  • Male