Researchers Pin Down Genetic Pathways Linked to CF Disease Severity

Posted: February 24, 2015 at 7:41 am

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Newswise CHAPEL HILL, NC Mutation of one gene is all it takes to get cystic fibrosis (CF), but disease severity depends on many other genes and proteins. For the first time, researchers at the UNC School of Medicine have identified genetic pathways or clusters of genes that play major roles in why one person with CF might never experience the worse kinds of symptoms while another person will battle severe airway infection for a lifetime.

The finding, published in the American Journal of Human Genetics, opens avenues of research toward new personalized or precision treatments to lessen pulmonary symptoms and increase life expectancy for people with cystic fibrosis.

Right now, there are drugs being developed to fix the function of the CFTR protein that is disrupted in cystic fibrosis, but even then, some patients will respond very well to therapy and some wont, said Michael Knowles, MD, professor of pulmonary and critical care medicine and senior author of the paper. Why is that? We think its the genetic background the pathways that we identified contain genes that likely interact with the main CFTR gene mutation.

Knowless team found that when these pathways or groups of genes are highly expressed, CF patients have less severe symptoms. When these pathways are expressed in lower amounts, patients experience a more severe form of the disease and are more likely to be hospitalized.

Wanda ONeal, PhD, associate professor of medicine and first author, said, Now that weve found these pathways, we need to dig into the biology to see how specific genes within them influence disease severity. This could help us not only to predict which patients will respond to a given therapy but it may also provide drug targets to lessen the severity of disease for all patients.

The CFTR gene was discovered in 1989, and since then researchers have found about 1,800 different mutations in the CFTR gene that cause cystic fibrosis. There is a new drug that works very well to correct a mutation found in about 4 percent of CF patients. There is still no FDA approved drug to correct the mutation found in about 70 percent of patients (called the DF508 mutation), though a drug company has recently shown that a combination therapy of two new drugs modestly improved lung function in some CF patients. Still, this combination therapy may not work or wouldnt work well enough for some patients, and the reason could be the complex interaction between the CFTR gene and the genetic pathways uncovered by Knowles, ONeal, and co-senior author Fred Wright, PhD, a professor of bioinformatics and director of the bioinformatics program at North Carolina State University.

In a normal epithelial cell, the CFTR gene creates the protein that transits from the cell nucleus to the cell membrane, where it then works to maintain proper lung function. As the protein transits, there are many genes that interact with it in various ways so that it can complete the journey to the membrane and work properly in the end. In CF patients with the DF508 mutation, the CFTR gene does not fold into its correct form and cannot make it to the cell surface. In order for CF patients to be out of the woods, the DF508 protein would need help from a complex network of genes and proteins to get to the membrane.

Over the past decade, Knowles has teamed with scientists from the United States and Canada to gather thousands of genetic and blood cell samples from CF patients. One of the research goals has been to identify genes and cellular proteins that often have subtle effects inside cells but that can produce dramatic differences in disease severity. Decades of research on protein functions has allowed genes to be grouped into pathways based on common biological roles.

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Researchers Pin Down Genetic Pathways Linked to CF Disease Severity

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