# Genetic Basis of Pulmonary Fibrosis

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $437,697

## Abstract

PROJECT SUMMARY
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...

## Key facts

- **NIH application ID:** 9928087
- **Project number:** 5P01HL092870-10
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** John Atlas Phillips III
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,697
- **Award type:** 5
- **Project period:** — → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928087

## Citation

> US National Institutes of Health, RePORTER application 9928087, Genetic Basis of Pulmonary Fibrosis (5P01HL092870-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9928087. Licensed CC0.

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