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. doi: 10.1164/rccm.201810-1891OC.

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. 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.

Keywords: disease risk alleles; genetic variants; idiopathic pulmonary fibrosis; rare variants; targeted resequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Case-Control Studies
  • Cellular Senescence / genetics*
  • DNA Helicases / genetics
  • Exoribonucleases / genetics
  • Female
  • GTPase-Activating Proteins / genetics
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study
  • High-Throughput Nucleotide Sequencing
  • Host-Pathogen Interactions / genetics*
  • Humans
  • Idiopathic Pulmonary Fibrosis / genetics*
  • Logistic Models
  • Male
  • Mucin-5B / genetics
  • Promoter Regions, Genetic / genetics
  • Pulmonary Surfactant-Associated Protein A / genetics
  • Pulmonary Surfactant-Associated Protein C / genetics
  • RNA / genetics
  • Sequence Analysis, DNA
  • Telomerase / genetics
  • Telomere-Binding Proteins / genetics

Substances

  • ABCA3 protein, human
  • ATP-Binding Cassette Transporters
  • FAM13A protein, human
  • GTPase-Activating Proteins
  • MUC5B protein, human
  • Mucin-5B
  • Pulmonary Surfactant-Associated Protein A
  • Pulmonary Surfactant-Associated Protein C
  • SFTPA2 protein, human
  • SFTPC protein, human
  • TINF2 protein, human
  • Telomere-Binding Proteins
  • telomerase RNA
  • RNA
  • TERT protein, human
  • Telomerase
  • Exoribonucleases
  • poly(A)-specific ribonuclease
  • RTEL1 protein, human
  • DNA Helicases