Featured Research

from universities, journals, and other organizations

Gene That Modifies Severity Of Cystic Fibrosis Lung Disease Found

Date:
March 4, 2009
Source:
Cincinnati Children's Hospital Medical Center
Summary:
Researchers have discovered a gene that modifies the severity of lung disease in people with the lethal genetic condition, cystic fibrosis, pointing to possible new targets for treatment, according to a new study in Nature. This is the first published study to use a genome-wide approach to look for genes that modify cystic fibrosis lung disease severity, said researchers.

Researchers have discovered a gene that modifies the severity of lung disease in people with the lethal genetic condition, cystic fibrosis, pointing to possible new targets for treatment, according to a new study in Nature.

Related Articles


Deleting this gene in mice confirmed its role in regulating inflammation and disease. After the animals' airways were infected with the bacterium that is a major cause of lung infection in cystic fibrosis, the mice experienced less inflammation and disease, said senior investigator Christopher Karp M.D., director of Molecular Immunology at Cincinnati Children's Hospital Medical Center.

Posted online by the journal Feb. 25 in advance of publication, it the first published study to use a genome-wide approach to look for genes that modify the severity of cystic fibrosis lung disease.

After analyzing the genetic makeup of nearly 3,000 people from two groups of cystic fibrosis patients – one from Johns Hopkins University and the other from the University of North Carolina and Case Western Reserve University – the 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 Dr. Karp. "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 wasn't on the radar screen of researchers looking for genetic modifiers of disease severity, although the gene had been linked to stress responses in muscle and other tissues, Dr. Karp said.

To further explore IFRD1's role in the disease process, the researchers studied mice in which the IFRD1 gene was knocked out. Researchers infected the airways of these animals with Pseudomonas aeruginosa, a common cause of airway infection in cystic fibrosis. The absence of IFRD1 resulted in delayed clearance of bacteria from the mice's airways, but also resulted in less inflammation and disease.

Although deleting IFRD1 blunted the inflammatory response of neutrophils to infection, it did not appear to affect other blood cells or compromise the overall functioning of the immune system. Also unaffected was the ability of mice to make blood cells, including neutrophils. Bone marrow transplantation studies in mice revealed that IFRD1 expression in blood cells, or the lack thereof, was central to these findings.

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.

"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 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.

Funding support for the study came from the National Cystic Fibrosis Foundation, the National Heart Lung and Blood Institute, the Wake Forest University Health Sciences Center for Health Genomics and the Austrian Science Fund.

Other institutions involved in the study include: the McKusick-Nathans Institute of Genetic Medicine and Department of Medicine at Johns Hopkins University School of Medicine, Baltimore; the Departments of Pediatrics and Genetics, Case Western Reserve University, Cleveland; the Cystic Fibrosis-Pulmonary Research and Treatment Center, University of North Caroline, Chapel Hill, N.C.; Biocenter, Division of Cell Biology at Innsbruck Medical University, Innsbruck, Austria; Oklahoma Medical Research Foundation and JK Autoimmunity Inc., Oklahoma City, Okla.; Wake Forest University Health Sciences, Winston-Salem, N.C.; The David Hide Asthma and Allergy Research Centre, Newport, Isle of Wight, UK; Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University.


Story Source:

The above story is based on materials provided by Cincinnati Children's Hospital Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Cincinnati Children's Hospital Medical Center. "Gene That Modifies Severity Of Cystic Fibrosis Lung Disease Found." ScienceDaily. ScienceDaily, 4 March 2009. <www.sciencedaily.com/releases/2009/02/090225132235.htm>.
Cincinnati Children's Hospital Medical Center. (2009, March 4). Gene That Modifies Severity Of Cystic Fibrosis Lung Disease Found. ScienceDaily. Retrieved December 19, 2014 from www.sciencedaily.com/releases/2009/02/090225132235.htm
Cincinnati Children's Hospital Medical Center. "Gene That Modifies Severity Of Cystic Fibrosis Lung Disease Found." ScienceDaily. www.sciencedaily.com/releases/2009/02/090225132235.htm (accessed December 19, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Friday, December 19, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

The Best Tips to Curb Holiday Carbs

The Best Tips to Curb Holiday Carbs

Buzz60 (Dec. 19, 2014) It's hard to resist those delicious but fattening carbs we all crave during the winter months, but there are some ways to stay satisfied without consuming the extra calories. Vanessa Freeman (@VanessaFreeTV) has the details. Video provided by Buzz60
Powered by NewsLook.com
Sierra Leone Bikers Spread the Message to Fight Ebola

Sierra Leone Bikers Spread the Message to Fight Ebola

AFP (Dec. 19, 2014) More than 100 motorcyclists hit the road to spread awareness messages about Ebola. Nearly 7,000 people have now died from the virus, almost all of them in west Africa, according to the World Health Organization. Video provided by AFP
Powered by NewsLook.com
Researchers Test Colombian Village With High Alzheimer's Rates

Researchers Test Colombian Village With High Alzheimer's Rates

AFP (Dec. 19, 2014) In Yarumal, a village in N. Colombia, Alzheimer's has ravaged a disproportionately large number of families. A genetic "curse" that may pave the way for research on how to treat the disease that claims a new victim every four seconds. Duration: 02:42 Video provided by AFP
Powered by NewsLook.com
Kids Die While Under Protective Services

Kids Die While Under Protective Services

AP (Dec. 18, 2014) As part of a six-month investigation of child maltreatment deaths, the AP found that hundreds of deaths from horrific abuse and neglect could have been prevented. AP's Haven Daley reports. (Dec. 18) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins