The overall goal of this project is to combine genetic and genomic findings in patients with idiopathic interstitial pneumonia (IIP) to develop and validate phenotypically anchored molecular signatures that serve to refine the diagnostic criteria for this group of complex diseases. IIP has traditionally been defined by objective clinical characteristics (history, physiology, radiography, and pathology). This approach splits out diseases that appear to be homogeneous including acute interstitial pneumonia (AIP), lymphocytic pneumonia (LIP), and cryptogenic organizing pneumonia (COP) but idiopathic pulmonary fibrosis (IPF), non specific interstitial pneumonia (NSIP), and a group of IIPs that do not fit a specific category remain heterogeneous in terms of overlapping patterns that often defies diagnostic labeling. Substantial evidence supports the concept that these latter categories of IIP, as currently defined, still comprise a heterogeneous phenotype in terms of pattern of presentation, outcome, and response to therapy. It is also possible that even those entities that appear to be homogeneous may in fact comprise mixed groups. For example, what appears clinically to be AIP may, in fact, represent an acute exacerbation of IPF that has hitherto experienced a very indolent and therefore clinically unrecognized course that has developed a rapid explosive phase. While the biological features of IIP are emerging, these molecular attributes (or signatures) that are prototypical of IIP have not yet been integrated with the traditional clinical diagnostic characteristics for these fibrosing interstitial pneumonias. In IIP, gene expression studies from our lab and others have demonstrated unique molecular signatures for some (IPF and familial forms of IIP) but not all (NSIP) forms of this disease. Given the overlapping classification of IIP subtypes and the likelihood that multiple genes play a role in the development of this group of diseases, this is not at all surprising. For instance, about 10% of patients with IIP develop disease due to mutations in either surfactant protein C or telomerase genes, presumably resulting in two distinct molecular signatures. We have recently performed a linkage study in 82 families with = 2 members with probable/definite IIP and have identified regions on chromosomes 10, 11, and 12 that likely contain genes contributing to familial forms of IIP, again presumably resulting in distinct molecular signatures. The compelling challenge is to combine genetic and genomic approaches in patients with IIP to define molecular phenotypes of IIP that can be used to distinguish the clinical aspects of this group of complex diseases. To address this challenge, we hypothesize that the IIP transcriptome is influenced by genetic variants and that, in combination with clinical characteristics, these molecular signatures can be used to refine the diagnostic criteria for this group of complex diseases. To test this hypothesis, we will combine the results of genome-wide RNA expression with regions/genes of interest from genetic studies to develop and validate phenotypically anchored molecular signatures for IIP and its subtypes.

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 overall goal of the proposed project is to combine genetic and genomic findings in patients with IIP to develop and validate molecular signatures that serve to refine the diagnostic criteria for this group of complex diseases;once established these molecular signatures of IIP could be tested in future studies to enhance early detection, to predict outcome, and to mould personalized therapeutic strategies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Program Officer
Gan, Weiniu
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Jewish Health
United States
Zip Code
Manichaikul, Ani; Sun, Li; Borczuk, Alain C et al. (2017) Plasma Soluble Receptor for Advanced Glycation End Products in Idiopathic Pulmonary Fibrosis. Ann Am Thorac Soc 14:628-635
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
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
Julian, Colleen G; Pedersen, Brent S; Salmon, Carlos Salinas et al. (2015) Unique DNA Methylation Patterns in Offspring of Hypertensive Pregnancy. Clin Transl Sci 8:740-5
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
Chung, Jonathan H; Chawla, Ashish; Peljto, Anna L et al. (2015) CT scan findings of probable usual interstitial pneumonitis have a high predictive value for histologic usual interstitial pneumonitis. Chest 147:450-459
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
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 147:460-464
Yang, Ivana V; Schwartz, David A (2015) Epigenetics of idiopathic pulmonary fibrosis. Transl Res 165:48-60
Yang, Ivana V; Pedersen, Brent S; Rabinovich, Einat et al. (2014) Relationship of DNA methylation and gene expression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 190:1263-72

Showing the most recent 10 out of 23 publications