Scientists find gene that modifies severity of cystic fibrosis lung disease

The study appeared online last week in advance of print publication in Nature. It is the first published study to search the entire genome looking for genes that modify the severity of cystic fibrosis lung disease.

“This is a good example of researchers with different expertise coming together and using the knowledge gained from mapping the human genome to make discoveries that improve our understanding of cystic fibrosis,” said Carl Langefeld, Ph.D., a study co-author and Wake Forest University School of Medicine researcher. “It may also help in the identification of targets for drug development and the development of tools for the earlier diagnosis of individuals with cystic fibrosis who are susceptible to severe lung disease.”

After analyzing the genetic makeup of nearly 3,000 cystic fibrosis patients, researchers found that small genetic differences in a gene called IFRD1 correlate with lung disease severity. While probing how the gene might alter the disease's course, researchers discovered the protein encoded by IFRD1 is particularly abundant in a type of white blood cell called neutrophils, and that it regulates their function. Part of the immune system, neutrophils are known to cause inflammatory damage to the airways of people with cystic fibrosis.

“Neutrophils appear to be particularly bad actors in cystic fibrosis,” said senior investigator Christopher Karp, M.D., the director of Molecular Immunology at Cincinnati Children's Hospital Medical Center. “They are important to the immune system's response to bacterial infection. In cystic fibrosis, however, neutrophilic airway inflammation is dysregulated, eventually destroying the lung.”

Although it's been known for 20 years that cystic fibrosis is caused by mutations in the CFTR gene, the molecular mechanisms that link these mutations to the generation of lung disease still remain unclear. Increasingly evident in recent years is that variations in other genes also play a role in controlling cystic fibrosis lung disease severity.

Prior to the current study, IFRD1 was not really considered by researchers looking for genetic modifiers of disease severity, although the gene had been linked to stress responses in muscle and other tissues.

To further explore IFRD1's role in the disease process, the researchers studied mice in which the IFRD1 gene was removed. Deleting the gene confirmed its role in regulating inflammation and disease. While the absence resulted in delayed clearance of bacteria from the airway, it also resulted in less inflammation and disease.

The researchers also studied blood samples from healthy human volunteers to verify the impact of genetic differences in IFRD1 on neutrophil regulation. They found that the same IFRD1 variations that modified cystic fibrosis lung disease severity also altered neutrophil function in the healthy volunteers.

In a finding that may be the basis for novel approaches to treating cystic fibrosis, the investigators also determined that IFRD1's regulation of neutrophil function depends on its interaction with histone deacetylases – enzymes important for regulating gene transcription. Additional research is needed to better understand this interaction before its potential role for treatment is known, researchers report.

“It's possible that IFRD1 itself could become a target for treatment, but right now it's a signpost to pathways for further study,” Karp said. “We want to find out what other genes and proteins IFRD1 interacts with, and how this is connected to inflammation in cystic fibrosis lung disease.”

According to the National Cystic Fibrosis Foundation, cystic fibrosis is an inherited chronic disease that affects the lungs and digestive systems of about 30,000 children and adults in the United States and 70,000 worldwide. The defect in the CFTR gene causes the body to produce unusually thick, sticky mucus that clogs the lungs and leads to life-threatening lung infections. It also obstructs the pancreas and stops natural enzymes from helping the body break down and absorb food.

In the 1950s, few children with cystic fibrosis lived to attend elementary school. Today, advances in research and medical treatments have allowed people to live into their 30s or 40s. Despite these advances, the norm remains an ongoing decline in pulmonary function.

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