During the initial funding period, we employed whole exome sequencing in 190 families and to date have identified rare variants in 5 new genes that are associated with familial interstitial pneumonia (FIP). These include telomere related genes RTEL1 and DKC1; the G protein-coupled receptor GPR87; the centromere gene CENPN; and SYDE1. While it is generally believed that genetic risk for FIP is inherited in an autosomal dominant (AD) fashion, pedigree modeling of our FIP kindreds now suggests that as many as 39% of families could have alternative modes of inheritance, including X-linked (XL) or autosomal recessive (AR). Evaluating genetic risk based on these alternative inheritance models offers promise for identifying additional genes that contribute to FIP risk, as illustrated by our finding of an XL DKC1 mutation in FIP. Although we have identified novel heterozygous rare variants in several genes that are associated with FIP during the initial funding period, our findings indicate that rare variants in a variety of genes (not a single gene or small set of genes) contribute to FIP risk. This issue, along with limitations in the genetic informativeness of many of our FIP kindreds, has necessitated new approaches and novel analytic methods for identifying genetic risk factors in FIP. Along with Dr. Nancy Cox, a new co-investigator in Project 2, we have begun to use Genotype-Tissue Expression (GTEx) datasets to build large-scale predictors of gene expression in human lungs and other tissues, which can be applied to identify genes involved in disease pathogenesis. We propose to use this approach coupled with BioVU, which is a unique resource at Vanderbilt that links de-identified medical records to genotyped DNA samples, to maximize informativeness of genetic studies in this proposal. In addition to studies in FIP, we believe it is important to broaden our focus by using next-generation sequencing techniques to determine the importance of the FIP-associated genes and pathways in the larger group of individuals with sporadic IPF. Based on a new collaborative arrangement with Genentech, whole genome sequencing is now feasible and will be pursued to develop a more complete understanding of genetic factors that underlie sporadic IPF. This project will investigate the hypothesis that development of FIP/IPF is influenced by multiple genetic factors that variably contribute to disease predisposition, including rare variants of major effect and common variants of minor effect. Identifying both types of disease-causing variants and the genes and biological pathways involved will elucidate critical mechanisms in the pathogenesis of FIP and sporadic IPF.
Specific aims are designed to: 1) identify rare variants associated with FIP that are inherited in an AD, AR, or XL manner; 2) investigate the contribution of rare, intermediate, and common genetic variations in FIP associated genes and pathways to sporadic IPF; 3) use GTEx datasets, BioVU, and advanced bioinformatics approaches to identify and prioritize candidate genes associated with FIP and sporadic IPF. Together with other projects in this program, these studies will enhance understanding of FIP/IPF by identifying new disease-associated genes and variants.
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 identify new targets for therapeutic intervention.
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