3 IPF Gene Variants Found in Large Genome-wide Analysis, Study Reports

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A large-scale analysis of multiple genome-wide studies has identified three new gene variants — mutations in DNA sequences — associated with idiopathic pulmonary fibrosis, a study reported.

Two of these genetic variants are not directly linked to fibrosis, or the scarring of lung tissue. However, the third gene variant is associated with a protein implicated in the production of collagen and the development of fibrosis.

In addition, a risk analysis excluding known IPF-related gene variants suggested there may be hundreds of unknown variants still to be discovered. 

The study, “Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis,” was published in the American Journal of Respiratory and Critical Care Medicine.

IPF is associated with a number of genetic and environmental factors. Identifying genes linked to the disease not only helps to improve scientists’ understanding about it, but also supports the development of new treatments.

Genome-wide association studies (GWAS) — used to pinpoint genes that may contribute to a person’s risk of developing a certain disease — have reported 17 common variants linked to IPF. The most strongly associated gene was the mucin gene, responsible for mucus production. However, as strong as this link is, it has been reported in only 35% of cases. Thus, it does not explain all IPF risk.

To find additional genes linked to IPF, researchers from the University of Leicester and the University of Nottingham, both in the United Kingdom, led a study that involved collaborators from more than 30 institutions across six countries. The goal was to assess and reanalyze data from independent GWAS studies that included more than 4,000 people with IPF and some 20,000 or more healthy individuals (controls). 

Through this large-scale analysis, the team identified three previously unknown genetic mutations implicated in IPF. 

The strongest signal came from a gene on chromosome eight encoding for the DEPTOR protein. DEPTOR inhibits mTOR kinase activity; changes in mTOR signaling are known to be associated with impairments in cell growth, cell survival, and inflammation.

The gene variant identified now was associated with reduced production of DEPTOR in lung tissue. Previous studies have implicated DEPTOR in fibrosis development, and reported that suppressing it stimulated collagen synthesis, or increased collagen production.

“The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis,” the researchers said.

The two other gene variants found were not linked directly to fibrosis. The MAD1L1 gene, found on chromosome seven, is involved in accurate chromosome segregation during cell division. Mutations in this gene have been linked to multiple cancers, including lung cancer. The KIF15 gene on chromosome three also was found to be linked to cell division processes.  

The team also confirmed 11 of the 17 previously reported genes associated with IPF

Along with the three new variants, 12 of the 14 IPF-linked genes found in the study were associated with one lung function characteristic, or more. The three new genes also were associated with a decreased forced vital capacity (FVC), a common measure of lung function. 

Finally, to determine the impact of IPF variants that have yet to be reported, a risk calculation was conducted that excluded the 14 known IPF-related variants. The risk scores showed that IPF is associated with hundreds, if not thousands, of unknown genetic variants linked to disease susceptibility.

“Genetic studies hold real promise in helping us find new treatments for IPF,” Louise Wain, PhD, a professor of respiratory research at the University of Leicester and a study co-author, said in a press release“The next step is to find out how these findings can enable us to find new and better treatments for IPF.”

Richard Allen, PhD, a pulmonary fibrosis research fellow at the University of Leicester and study co-author, said the “exciting” discoveries help improve understanding of the disease.

“Hopefully this research will help in the development of treatments,” Allen said.

“To find a cure, it is vital that we understand the genetic changes associated with the process of lung fibrosis,” said Steve Jones, chair of Action for Pulmonary Fibrosis, which helped fund the study, along with the National Institute for Health Research (NIHR) in the U.K. and the British Lung Foundation.

“This path-breaking research has identified three genes, which could lead to new treatments bringing hope to the large number of people around the world living with the disease,” Jones said.