# Genotype-Phenotype Interactions in Familial Interstitial Pneumonia

> **NIH NIH P01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $446,129

## Abstract

PROJECT SUMMARY
Ascertainment of kindreds with familial interstitial pneumonia (FIP) has proven to be a valuable resource for
studying genetic susceptibility and underlying mechanisms that promote interstitial lung disease. Studies of
FIP kindreds during the current funding period have led to several important findings, including the observation
that rare variants (RVs) in a variety of genes can predispose to FIP. Based on whole exome sequencing
(WES) from FIP patients during the current funding cycle, we have identified novel RVs in several genes that
we believe are causative in FIP, including the telomerase pathway genes DKC1 and RTEL1, a G protein-
coupled receptor GPR87, a centromere gene CENPN, and a gene of unknown function SYDE1. Preliminary
studies to examine the functional importance of RVs in these genes have linked RTEL1 and GPR87 to the p53
pathway, suggesting that this pathway may integrate at least a portion of our genetic findings. To identify
additional gene candidates, we used an unbiased approach to uncover pathways that were over-represented
in the set of candidate RV-containing genes implicated by WES. Using this approach, two interrelated
pathways containing microtubule/cilia genes and centrosome genes were found to be markedly over-
represented. Together, our preliminary data point to a defined set of interacting pathways that show promise
for containing RVs that predispose to FIP. The primary goal of this project during the current funding period
was to identify, enroll, and phenotype members of families at risk for developing FIP. To date, we have
enrolled 372 asymptomatic first-degree relatives of FIP patients in this ongoing cohort study and obtained
blood samples and high resolution CT (HRCT) scans, as well as 100 bronchoscopies. In addition, through our
ongoing collaboration with Dr. Schwartz (PI of Project 3), we have recently enrolled another 503 individuals at
risk for FIP in this ongoing cohort study. Together, this cohort of 875 asymptomatic individuals provides a
powerful resource to identify the earliest manifestations of FIP, better define the natural history of FIP, and
determine endophenotypes based on genetic predisposition. In this competitive renewal, we hypothesize that
damaging rare genetic variants in several inter-related pathways (including telomere genes,
microtubule/cilia/centrosome genes, and p53-related genes) predispose to FIP through a common mechanism
related to altered cell survival/proliferation. Specific aims are designed to: 1) evaluate genes with candidate
rare genetic variants identified in FIP families and prioritize them for functional studies, 2) perform functional
analysis of candidate rare genetic variants in targeted pathways, and 3) characterize genotype-phenotype
relationships in individuals at risk for FIP. By validating and testing the function of new disease-associated
alleles and using this information to determine genotype-phenotype relationships in individuals enrolled in ou...

## Key facts

- **NIH application ID:** 9928084
- **Project number:** 5P01HL092870-10
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Timothy S. Blackwell
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $446,129
- **Award type:** 5
- **Project period:** — → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928084

## Citation

> US National Institutes of Health, RePORTER application 9928084, Genotype-Phenotype Interactions in Familial Interstitial Pneumonia (5P01HL092870-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9928084. Licensed CC0.

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