Collaboration Seeks Genetic Clues to Chronic Lung Disease

Idiopathic pulmonary fibrosis (IPF) is a disease that causes scarring on the lungs. Over time, as more scarring occurs, patients experience decreased lung function and difficulty breathing. Once diagnosed, most patients die within five years. 

Currently, only two FDA-approved treatment options are available to help slow the progression of the disease. A multidisciplinary team of Duke clinicians, bioinformaticians, statisticians, and researchers with high-throughput genomics expertise is hoping their work will lead to more treatment options for IPF patients that will improve both their quantity and quality of life. 

The team, led by Jamie Todd, MD, assistant professor of medicine; Megan Neely, PhD, assistant professor of biostatistics and bioinformatics; Andrew Allen, PhD, professor of biostatistics and bioinformatics; Tim Reddy, PhD, associate professor of biostatistics and bioinformatics; and Greg Crawford, PhD, professor in pediatrics, is investigating how a person’s genetic makeup can affect how quickly or slowly the disease progresses in individuals.  

“Our hope,” Todd said, “is that we might identify new genes that haven’t previously been associated with contributing to IPF disease or IPF disease behaviors.” If successful, they might be able to find new genetic influences, which could lead to new therapeutic targets that slow the progression of the disease. 

Jamie Todd, MD; Megan Neely, PhD; Andrew Allen, PhD; Tim Reddy, PhD, Greg Crawford, PhD
From Left: Jamie Todd, MD; Megan Neely, PhD; Andrew Allen, PhD; Tim Reddy, PhD; Greg Crawford, PhD

They are utilizing an IPF observational registry housed in the Duke Clinical Research Institute (DCRI) that includes clinical data and biological samples from over 1,000 patients with IPF. The registry includes data about patient lung function over time, which can help researchers better understand how the disease behaves in individuals. They can measure whether lung function declines or stays the same, how often a patient is admitted to the hospital with a flareup, and whether that patient survives. 

Whole genome sequencing has also been completed for every patient in the IPF cohort. “We’ve identified several rare protein coding variants that associate with the risk of having the disease,” Todd said.  

Protein coding variants are helpful, but they don’t paint a complete picture of the disease, so the team is diving into variations in the noncoding sequences of the genome, which affects gene expression. “The genome is a very big place to look for clues to better understand IPF.” Crawford said. “For this project, we are narrowing the search space by looking at gene regulatory elements that turn genes on or off in cells that make up the lung.”  

Allen added: “What we are attempting to do is bring noncoding sequence into the orbit of genes and aggregate rare variation and common variation.”  

Usually in genomic studies, researchers look at patient cells that they think can model a disease and then try to manipulate the cells. “But those cells all have their own genome and don’t represent the genetic variants an individual patient might have,” Reddy said. “By getting DNA from patients and assaying that, we can ask questions about how the unique genetic makeup of these individuals might be acting through gene regulation to contribute to IPF.” 

Using STARR-seq, a reporter gene assay, the team can identify potential gene regulatory contributions to characterize the genetic variation in a subset of patients with IPF. “What’s distinct about these reporter assays,” Reddy said, “is it gives us an opportunity to measure how an individual’s genome acts to regulate genes.” 

Allen is developing methods to analyze the data from STARR-seq. “Once we have that,” Allen said, “we’ll not only have what part of the genome is related to what gene, but also what effect the variants in those regions of the genome likely have on regulatory activity.”  

From there, they will be able to aggregate rare variation within those regions and look for an enrichment or depletion of this functionally active variation of certain genes.  

The project started in June 2022 and runs for two years. By the end of that time, the researchers hope to be able to discover the impact of noncoding variation in the regulatory regions of the genome on gene expression and IPF and how those two things relate to someone’s disease behavior.  

“There’s quite a bit known about rare and common genetic variants that influence IPF disease susceptibility,” Todd said, “but no one has been looking at how the non-coding genome influences IPF disease behavior. This research should help provide some answers.”  

Since IPF is a scarring disease, it will likely be a challenging disease to cure.  

“Stopping the scarring process is going to take a multi-targeted approach,” Todd said. And while she isn’t optimistic that there will ever be a cure for IPF, she is hopeful that we may someday have new and better options for treatment.