PROJECT 3: The goal of this proposal is to discover genetic variants that are central to the development of idiopathic interstitial pneumonia (IIP), including the most common and severe form known as idiopathic pulmonary fibrosis (IPF). Evidence for a genetic basis of IIP is substantial. Rare mutations in genes that maintain telomere length (TERT and TERC) have been reported in familial interstitial 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 (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. Although controversial, an association of herpesvirus with IPF has been developed, most clearly with Epstein Barr Virus (EBV);however, there is evidence that other viruses may be relevant. Thus, we hypothesize that combinations of genetic 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 of the genes/loci identified in FIP by testing the significance of genetic variants within these genes and loci in subjects with sporadic IIP and controls;3) comprehensively assess the presence of viruses in lung tissue from study subjects with sporadic IIP and controls;and 4) identify gene-environment (cigarette smoking and viruses) interactions 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 initial 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 biological-physiological phenotype by using environmental exposures. Using this approach, we will elucidate important genetic factors in IIP and determine how gene-environment interactions impact pathogenesis.
Interstitial lung diseases, including the idiopathic interstitial pneumonias, are a substantial cause of morbidity and mortality for which there are no effective treatments. In this program, we will study the genetics and underlying biological mechanisms that lead to progressive fibrosis in the lungs. Our integrated approach will lead to new concepts in disease pathogenesis and identification of novel treatment strategies.
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|Kropski, Jonathan A; Young, Lisa R; Blackwell, Timothy S et al. (2017) Reply: The Genetic Diagnosis of Interstitial Lung Disease: A Need for an International Consensus. Am J Respir Crit Care Med 195:1539-1540|
|Kropski, Jonathan A; Reiss, Sara; Markin, Cheryl et al. (2017) Rare Genetic Variants in PARN Are Associated with Pulmonary Fibrosis in Families. Am J Respir Crit Care Med 196:1481-1484|
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|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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