Study Information

 

 

 

The overall goal of this proposal is to discover genetic variants that are central to the development of idiopathic interstitial pneumonia (IIP).  We plan to discover loci and genes that predispose individuals to develop IIP by initially studying the familial form of IIP (FIP), validating these findings in sporadic IIP, and then determining how cigarette smoke and viruses modify these disease associated gene variants.

 

 

This project is conducted in 3 stages, with each stage focusing on an independent population of subjects with IIP. 

• First stage: use a linkage approach in families with 2 or more cases of IIP (FIP) to identify genes and loci associated with the most genetic presentation of this disease.
• Second stage: use association testing among study subjects with sporadic IIP and controls to determine the validity of the genes and loci that are identified in the first stage.
• Third stage: explore how these gene variants are influenced by cigarette smoking and viral infection in an independent population of subjects with IIP and controls.

 

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.

 

 

We have performed a limited 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 thought to be potentially associated with occupational exposures, and among cigarette smokers.

 

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.

 

We plan to address our hypothesis by pursuing the following specific aims.

• Perform a linkage study in affected individuals with familial IIP (FIP). Among families with FIP we are performing linkage studies to identify the genes and loci that are associated with the familial form of IIP. The variants detected will then be genotyped within the familial cohort.
• Determine the validity of the genes/loci identified in this study and other associated research by testing the significance of genetic variants within these genes and loci in subjects with sporadic IIP and controls.
• Comprehensively assess the presence of viruses in lung tissue from study subjects with sporadic IIP and controls. We will use a DNA microarray-based strategy to screen for viruses from all known viral families and viruses using lung tissue from subjects with sporadic IIP.
• Identify gene-environment interactions in IIP. We are testing for gene-environment interactions with and without a main genetic effect. We are also exploring whether these risk factors are associated with phenotypic subtypes of this complex disease, either individually or collectively.