Finding opens avenues of research toward precision treatments to boost life expectancy for CF patients

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 won't," said Michael Knowles, MD, professor of pulmonary and critical care medicine and senior author of the paper. "Why is that? We think it's the genetic background - the pathways that we identified contain genes that likely interact with the main CFTR gene mutation."

Knowles's 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 O'Neal, PhD, associate professor of medicine and first author, said, "Now that we've 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 wouldn't 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, O'Neal, 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.

For this current study, Knowles and O'Neal used gene expression data from the cells collected from 750 patients gathered over the past decade from 40 sites across the United States. Along with Wright and other authors, they analyzed data on more than 4,000 pathways to find pathways that identified severe CF patients as compared to mild CF patients. They found significant genetic variation in only broad types of pathways: endomembrane pathways and HLA pathways.

This finding was telling because endomembrane genes are responsible for transporting the DF508 protein from the cell nucleus to the cell membrane and for regulating the way that proteins such as CFTR are folded into the proper functioning form. The HLA genes are widely known to have roles in immune function; they're important for protection against pathogens, such as Pseudomonas - the commonly seen bacteria that causes pneumonia in CF patients.

According to this research, disease severity depends on how genes in these pathways function.

"Now, we'd like to continue to evaluate the response of patients to new treatments," Knowles said. "We want to know if people who respond well have higher expression of these genetic pathways. If so, then we're really on the heels of personalized approaches to treating CF patients at the level of their genes to lessen the severity of often debilitating symptoms."