Asthma Gene Clusters Identified

Findings could lead to new treatment based on individual genetic profiles

Tuesday, February 08, 2005

Children who suffer from acute asthma attacks share a genetic profile that appears to be unique to these children, according to a new study by researchers at Cincinnati Children's Hospital Medical Center. The discovery opens the door to the possibility of designing treatments specifically tailored to children who suffer from the severest forms of asthma.

The findings appear in the February 10 issue of the Journal of Allergy and Clinical Immunology information, articles.

The study is based on an Affymetrix "GeneChip" analysis of RNA isolated from the nasal epithelium of children who have an acute case of asthma or asthma stabilized with medication. The analysis revealed two distinct gene expression profiles in these groups of children, according to Gurjit K. Khurana Hershey, MD, PhD, director of the Center for Translational Research in Asthma and Allergy at Cincinnati Children's and senior author of the study.

"We found that children who were having an acute asthma attack had a gene expression profile that was clearly different from those seen in someone with stable (controlled) asthma. The amazing thing was that the gene expression profiles were consistent across patients, despite the likely differences with respect to the cause of asthma," she said.

Asthma is the most common chronic disease of childhood affecting 20 million Americans, according the Centers for Disease Control. Experts know that environmental factors can lead to asthmatic conditions in children, but they also know that genetics contributes to susceptibility. There are no cures for asthma, but it can be controlled with treatment.

To date, researchers have identified individual genes involved in asthma, but this is the first time that clusters of known genes have been identified as being activated in acute forms of childhood asthma.

Dr. Hershey said the findings open the door to the possibility of developing treatments based on the unique genetic profile of patients. For example, specific therapies for acute asthma could be targeted to genes that are seen in acute, but not stable asthma. Also, in addition to differentiating between an acute and stable asthma attack, the genetic profile may be useful in identifying an imminent asthma attack.

Researchers examined 54,675 genes. They discovered eight gene clusters in all, consisting of 161 genes. At least one cluster was identified that was comprised of genes active in acute asthma, but not stable asthma. They also identified gene clusters that were active in stable asthma, but not the acute form of the disease.

"Now that we know what genes are turned on during an asthma attack, we will conduct studies to see if this genetic profile can be used to customize care. The current methods of treatment primarily consist of anti-inflammatory drugs, which may not be optimal for acute attacks," Dr. Hershey said.

Previous studies using microarray technology have been conducted using RNA from adults with asthma, but this approach has not been successfully used in human studies involving children with asthma. In pediatrics, it is difficult to obtain tissue in sufficient quantities for analysis, especially during an asthma attack. But because asthma begins in childhood, the genes identified in adults may not reflect genes involved in childhood asthma, she said.

This study exclusively focused on genes associated with epithelial cells. Genes associated with mucosa and underlying cells are likely to be involved as well.

Dr. Hershey is expanding her research in cooperation with the Computational Medicine Center (CMC), a research partnership with Cincinnati Children's and the University of Cincinnati College of Medicine. The center specializes is combining computational resources with medicine and genetics in order to customize care for patients based on the patient's individual genetic makeup.

"Dr. Hershey's research is a good example of research that we believe will benefit patients, based on the use of novel algorithms and analysis from computational medicine. In this study, we show that asthma is controlled by two different genetic profiles. Now, in computational medicine, we will combine all of our clinical knowledge of disease with information from genetic and genomic data analyses. This, in turn, will lead to customized care based on a patient's personal needs," according to Bruce Aronow, PhD, co-director of the CMC and co-author of the study.

"Our ultimate goal is to provide physicians the data they need to prescribe the most effective medications, discover new therapies and to help prevent disease," he said.

Ultimately, Dr. Hershey's goal would be to identify gene profiles that are expressed during asthma that are exacerbated by different factors, such as exercise, viral infection or allergic triggers. In doing so, physicians will be in a better position to assess and treat a patient's asthma with greater precision.

"As we learn more about disease and how patients respond to treatment, we will eventually be able to develop customized therapy for patients with different gene expression profiles," she said.

The study was funded by the National Institutes of Health and the University of Cincinnati Center for Environmental Genetics.

Cincinnati Children's is a 423-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to transforming the way health care is delivered by providing care that is timely, efficient, effective, family-centered, equitable and safe. It ranks third nationally among all pediatric centers in research grants from the National Institutes of Health. The Cincinnati Children's vision is to be the leader in improving child health.