UNC. US: New findings from the UNC School of Medicine may shed light on why
cystic fibrosis patients with the same genetic mutation can have
different disease severity and may react differently to medications.
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.”
This research was funded by the National Institutes of Health, the
U.S. Cystic Fibrosis Foundation, the Canadian Institutes of Health
Research, and CF Canada.