The study, “Novel idiopathic pulmonary fibrosis susceptibility variants revealed by deep sequencing,” was published in the journal ERJ Open Research.
The existence of a genetic cause underlying IPF development is supported by researchers’ knowledge of familial forms of the disease — and given that IPF can co-occur within several rare genetic disorders. However, how genetic alterations are linked to disease risk is still unknown.
In a previous study, researchers found that the change of a single nucleotide — the building blocks of DNA — in the sequence of the MUC5B gene represented a strong risk factor for IPF. Identified as rs35705950, this mutation can be found in approximately 50% of people with IPF. It is known to increase risk of disease progression by up to 30%.
Supported by these findings, U.S. and Spanish researchers performed a deeper genetic analysis. They aimed to find additional genetic variations in candidate genes that could be linked to a higher risk of IPF.
The team sequenced DNA samples from 181 IPF patients, mean age 67 years at diagnosis, who experienced symptoms of dyspnea (shortness of breath) for at least 3 months. The majority of the patients (76.2%) had participated in the University of Chicago natural history study (NCT00470327). A total 22 patients had enrolled in the Correlating Outcomes with biochemical Markers to Estimate Time-progression study (COMET, NCT01071707), and 21 had participated in the AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis (ACE-IPF) study (NCT00957242).
The new genetic analysis identified 36 single nucleotide variants (SNVs) associated with the risk for IPF. The strongest was a MUC5B variant called s35705950 that was associated with a 4.9-fold higher risk of IPF development.
Researchers also found two novel SNVs, named rs34815853 and rs34474233, in the MUC5AC gene, which were predicted to change the production of the encoded protein. rs34815853 was associated with a 3.37-times increased risk for IPF, while rs34474233 was linked to a 3.39-times increased risk.
Exacerbated secretion of mucins, like those produced by the MUC5AC and MUC5B genes, is a common feature of inflammatory respiratory conditions. The variant in the MUC5B gene also led to increased expression of this gene in lung cells, but “the exact mechanistic links between the enhanced production of this mucin and the development of IPF are incompletely understood,” the researchers said.
The investigators further validated that the presence of these genetic variants were linked to IPF risk by performing new analysis of DNA samples of 602 IPF patients and 3,366 healthy controls, stored at a U.K. Biobank.
“This study reinforces the significant IPF associations of these loci [different genes] and implicates MUC5AC as another key player in IPF susceptibility,” the researchers concluded.