The purpose of this proposal is to discover genetic variants that are central to the development of fibrosing interstitial lung diseases (fILD). Since both genetic variants and the environment increase the risk of disease development in fILD, we seek to comprehensively identify genetic variants associated with fILD by considering environmental exposures while studying the genetics of this group of complex diseases. The fILD study populations included in this proposal (familial interstitial pneumonia (FIP), sporadic idiopathic interstitial pneumonia (IIP), and asbestosis) will enable us to discover genetic variants that are associated with fILD while spanning a spectrum of genes that confer susceptibility to fILD and are increasingly likely to be influenced by environmental exposures. Evidence for a genetic basis of fILD is substantial. fILD has been associated with pleiotropic genetic disorders, and at least 3% of cases of IIP have a first degree relative with a similar illness. Rare mutations in genes that maintain telomere length (TERT and TERC) have been reported to be associated with the development of FIP (defined as e 2 cases of IIP in one family) and idiopathic pulmonary fibrosis (IPF), the most common form of IIP. Two families with FIP have been shown to have disease-associated mutations in surfactant protein C. We have performed a linkage study in 82 families with FIP, and have identified linked regions on chromosomes 10, 11, and 12. Furthermore, we have found common variants in MUC5AC (chr11 positional candidate) that are associated with both FIP and IPF. Approximately 40% of families with FIP have discordant types of IIP among family members, suggesting that IIP may be caused by common gene variants that are altered phenotypically by environmental exposures. In fact, FIP and IPF can be influenced by environmental exposures, occurring more frequently in males (probably due to occupational exposures), and among cigarette smokers. IPF is also associated with exposure to metal or wood dust. Occupational exposure to asbestos can cause fILD that is indistinguishable from the histology of IPF (usual interstitial pneumonia, UIP). We have found that among patients with FIP, the chr11 LOD score is strongly influenced by cigarette smoking. Thus, we hypothesize that fILDs are caused by multiple genetic variants, acting independently or in combination with environmental exposures, and that the same genetic variants can lead to different forms of fILD. We plan to identify the genetic causes of fILDs by performing a genome-wide association study in familial and sporadic IIP and asbestosis, and determining the genetic variants associated with these diseases. In addition, we will examine the generalizability of these fILD genetic variants to other ethnic groups and in families of individuals with FIP. These approaches will identify genetic variants that are common to lung fibrosis, and genetic variants that are more unique to asbestos exposure and/or cigarette smoke.

Public Health Relevance

Idiopathic interstitial pneumonia (IIP) represents a broad spectrum of chronic fibrosing lung conditions that can lead to untreatable respiratory failure. While substantial progress has been made in understanding the clinical, radiological, and pathological manifestations of these disorders, it remains difficult for the clinician to predict the clinical course or the response to therapy for the subtypes of IIP, particularly from individual to individual with the same diagnosis. The purpose of this proposal is to discover genes and gene variants that are central to the development of fibrosing interstitial lung diseases (fILD);once established these genetic risks for fILD could be tested in future studies to enhance early detection, to predict outcome, and to mould personalized therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097163-04
Application #
8305033
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Gan, Weiniu
Project Start
2011-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$1,654,527
Indirect Cost
$352,720
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Fingerlin, Tasha E; Zhang, Weiming; Yang, Ivana V et al. (2016) Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet 17:74
Nakano, Yasushi; Yang, Ivana V; Walts, Avram D et al. (2016) MUC5B Promoter Variant rs35705950 Affects MUC5B Expression in the Distal Airways in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:464-6
Mathai, Susan K; Pedersen, Brent S; Smith, Keith et al. (2016) Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:1151-60
Chung, Jonathan H; Peljto, Anna L; Chawla, Ashish et al. (2016) CT Imaging Phenotypes of Pulmonary Fibrosis in the MUC5B Promoter Site Polymorphism. Chest 149:1215-22
Kliment, Corrine R; Araki, Tetsuro; Doyle, Tracy J et al. (2015) A comparison of visual and quantitative methods to identify interstitial lung abnormalities. BMC Pulm Med 15:134
Yang, Ivana V; Schwartz, David A (2015) Epigenetics of idiopathic pulmonary fibrosis. Transl Res 165:48-60
Cogan, Joy D; Kropski, Jonathan A; Zhao, Min et al. (2015) Rare variants in RTEL1 are associated with familial interstitial pneumonia. Am J Respir Crit Care Med 191:646-55
Liptzin, Deborah R; Watson, Alan M; Murphy, Elissa et al. (2015) MUC5B expression and location in surfactant protein C mutations in children. Pediatr Pulmonol 50:1270-6
Peljto, Anna L; Selman, Moises; Kim, Dong Soon et al. (2015) The MUC5B promoter polymorphism is associated with idiopathic pulmonary fibrosis in a Mexican cohort but is rare among Asian ancestries. Chest 147:460-4
Steele, Mark P; Luna, Leah G; Coldren, Christopher D et al. (2015) Relationship between gene expression and lung function in Idiopathic Interstitial Pneumonias. BMC Genomics 16:869

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