Gene modifies severity of cystic fibrosis lung disease
Cystic fibrosis, one of the most common life-shortening congenital diseases, affects children's lungs, intestines and pancreas. While it is understood to be caused by a defect in a single gene that causes the organs to become clogged with thick mucus, an international team of scientists has now identified a gene that modifies the severity of lung disease in people with cystic fibrosis. Their discovery, published in the journal Nature, could lead to new targets for treatment. According to the scientists, the study helped to strengthen cooperation amongst researchers and raising awareness about cystic fibrosis. '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 co-author Dr Carl Langefield of Wake Forest University School of Medicine. '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,' he added. The group of scientists evaluated the genetic makeup of approximately 3,000 cystic fibrosis patients. They discovered that small genetic differences in the IFRD1 (interferon-related developmental regulator 1) gene correlated with the severity of lung disease. The researchers also found that a protein encoded by IFRD1 is particularly abundant in neutrophils (a type of white blood cell) and regulates their function. Neutrophils have been identified as triggering inflammatory damage in the airways of people suffering from cystic fibrosis. 'Neutrophils appear to be particularly bad actors in cystic fibrosis,' explained Dr Christopher Karp from the Molecular Immunology at Cincinnati Children's Hospital Medical Center in the US, the senior investigator in this study. '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.' Past studies have shown that mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene trigger cystic fibrosis but questions remained over the molecular mechanisms that link these mutations to the generation of lung disease. According to the study, the severity of cystic fibrosis lung disease can be controlled by the variations in other genes. The scientists assessed mice whose IFRD1 gene was removed and confirmed its role in regulating inflammation and disease. Bacteria were not quickly cleared away from the airway when the gene was missing. By checking the blood samples of healthy human volunteers, the team discovered that the same IFRD1 variations that altered the severity of cystic fibrosis lung disease also changed neutrophil function in the volunteers. They also found that IFRD1's regulation of neutrophil function depends on its interaction with the class of enzymes called histone deacetylases. The scientists said more information about this interaction is needed to understand its potential role in treating the disease. 'It's possible that IFRD1 itself could become a target for treatment, but right now it's a signpost to pathways for further study,' Dr Karp explained. '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.' Cystic fibrosis affects 70,000 people worldwide and there is no known cure. Experts say the predicted median age of survival for a person with cystic fibrosis is 37 years, but with the introduction of new treatments this number could rise to 40 or even 50. Other institutions involved in the study were Innsbruck Medical University in Austria and the David Hide Asthma and Allergy Research Centre, Newport, Isle of Wight in the UK.
Countries
Austria, United Kingdom