PROJECT 3: The goal of this proposal is to discover genetic variants that are central to the development of idiopathic interstifial pneumonia (IIP), including the most common and severe form known as idiopathic pulmonary fibrosis (IPF). Evidence for a genefic basis of IIP is substanfial. Rare mutafions in genes that maintain telomere length (TERT and TERC) have been reported in familial interstifial pneumonia (FIP). Two families with FIP have been shown to have mutations in surfactant protein C. We have performed a limited linkage study in 82 families with FIP, and have identified linked regions on chromosomes 10, 11, and 12. Further, we have found common variants in MUC5AC (chrl 1 positional candidate) that are associated with both FIP and IPF. Approximately 40% of families with FIP have discordant types of IIP among family members, suggesfing 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. Although controversial, an associafion of herpesvirus with IPF has been developed, most cleariy with Epstein Barr Virus (EBV);however, there is evidence that other viruses may be relevant. Thus, we hypothesize that combinations of genefic variations or polymorphisms interact with cigarette smoke and/or viruses to predispose individuals to the clinical development of pulmonary fibrosis.
Specific aims for this project are to: 1) perform a linkage study in affected individuals with familial IIP;2) determine the validity ofthe genes/loci identified in FIP by tesfing the significance of genefic variants within these genes and loci in subjects with sporadic IIP and controls;3) comprehensively assess the presence of viruses in lung fissue from study subjects with sporadic IIP and controls;and 4) identify gene-environment (cigarette smoking and viruses) interacfions in IIP. This project will be conducted in 3 separate stages with each stage focusing on an independent population of subjects with IIP. The overarching concept is that the inifial focus on FIP will identify genetic variants that result in relatively large effects that should be generalizable to sporadic IIP and will be even more pronounced when we narrow the biologicalphysiological phenotype by using environmental exposures. Using this approach, we will elucidate important genefic factors in IIP and determine how gene-environment interacfions impact pathogenesis.

Public Health Relevance

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Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL092870-01A1
Application #
7770516
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2010-01-19
Project End
2014-12-31
Budget Start
2010-01-19
Budget End
2010-12-31
Support Year
1
Fiscal Year
2010
Total Cost
$579,110
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Benjamin, John T; van der Meer, Riet; Im, Amanda M et al. (2016) Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development. Am J Pathol 186:1786-800
Saxon, Jamie A; Cheng, Dong-Sheng; Han, Wei et al. (2016) p52 Overexpression Increases Epithelial Apoptosis, Enhances Lung Injury, and Reduces Survival after Lipopolysaccharide Treatment. J Immunol 196:1891-9
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
Claar, Dru D; Larkin, Emma K; Bastarache, Lisa et al. (2016) A Phenome-Wide Association Study Identifies a Novel Asthma Risk Locus Near TERC. Am J Respir Crit Care Med 193:98-100
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
Kropski, Jonathan A; Young, Lisa R; Cogan, Joy D et al. (2016) Genetic Evaluation and Testing of Patients and Families with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med :
Richmond, Bradley W; Brucker, Robert M; Han, Wei et al. (2016) Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency. Nat Commun 7:11240
Nevel, Rebekah J; Garnett, Errine T; Worrell, John A et al. (2016) Persistent Lung Disease in Adults with NKX2.1 Mutation and Familial Neuroendocrine Cell Hyperplasia of Infancy. Ann Am Thorac Soc 13:1299-304

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