Novel gene variant found in severe childhood asthma

An international scientific team has discovered a gene associated with a high risk of severe childhood asthma. The specific gene variant may be an actual cause of this form of asthma, a leading cause of hospitalization in young children.

“Because asthma is a complex disease, with multiple interacting causes, we concentrated on a specific phenotype—severe, recurrent asthma occurring between ages two and six,” said co-lead author of the study, Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia (CHOP). “Identifying a risk susceptibility gene linked to this phenotype may lead to more effective, targeted treatments for this type of childhood asthma.”

The study, published today in Nature Genetics, includes collaborators from centers in five countries. The corresponding author, Klaus Bonnelykke, M.D., Ph.D., is from the University of Copenhagen in Denmark. Hakonarson’s collaborators from CHOP are Patrick Sleiman, Ph.D., and Michael March, Ph.D.

The study team performed a genome-wide association study (GWAS) on DNA from Danish national health registries and the Danish National Screening Biobank. In the discovery phase of their study, they compared genomes from 1,173 children aged 2 to 6 years from the Copenhagen Prospective Study on Asthma in Childhood (COSPAC) with genomes from 2,522 adult and pediatric control subjects without asthma.

In addition to finding further evidence for four genes previously implicated as asthma susceptibility genes, the researchers identified a novel gene, CDHR3, which is particularly active in epithelial cells lining the surfaces of airways. The study team then replicated their findings using data from other children of both European and non-European ancestry.

“Asthma researchers have been increasingly interested in the role of the airway epithelium in the development of asthma,” said Hakonarson, a pediatric pulmonologist. “Abnormalities in the epithelial cells may increase a patient’s risk to environmental triggers by exaggerating immune responses and making the airway overreact. Because the CDHR3 gene is related to a family of proteins involved in cell adhesion and cell-to-cell interaction, it is plausible that variations in this gene may disrupt normal functioning in these airway cells, and make a child vulnerable to asthma.”

Asthma is a reversible obstructive lung disease, caused by increased reaction of the airways to various stimuli. It is a chronic inflammatory condition with acute exacerbations. Asthma can be a life-threatening disease if not properly managed.

  Asthma is one of the most common chronic disorders in childhood, currently affecting an estimated 7.1 million children under 18 years; of which 4.1 million suffered from an asthma attack or episode in 2011.

  An asthma episode is a series of events that results in narrowed airways. These include: swelling of the lining, tightening of the muscle, and increased secretion of mucus in the airway. The narrowed airway is responsible for the difficulty in breathing with the familiar “wheeze”.

Novel gene variant found in severe childhood aSthma    Asthma is characterized by excessive sensitivity of the lungs to various stimuli. Triggers range from viral infections to allergies, to irritating gases and particles in the air. Each child reacts differently to the factors that may trigger asthma, including:
        respiratory infections and colds
        cigarette smoke
        allergic reactions to such allergens as pollen, mold, animal dander, feather, dust, food, and cockroaches
        indoor and outdoor air pollutants, including ozone and particle pollution
        exposure to cold air or sudden temperature change

  Secondhand smoke can cause serious harm to children. An estimated 400,000 to one million children with asthma have their condition worsened by exposure to secondhand smoke.

Novel gene variant found in severe childhood asthma Hakonarson said that the current findings are consistent with previous investigations by CHOP’s Center for Applied Genomics, suggesting that other genes linked to childhood asthma play a role in oversensitive immune reactions.

Hakonarson added that further studies are needed to better understand how the CDHR3 gene may function in asthma, with the eventual goal of using such knowledge to design better treatments for children with severe cases of this disease.

Support for this study came from the Danish Medical Research Council and an Institutional Development Fund grant from The Children’s Hospital of Philadelphia.


What are the signs and symptoms of asthma in children?
The most common symptoms of childhood asthma are coughing and wheezing.

  Coughing is typically non-productive and can frequently be the only symptom. When it is the only symptom, this is termed cough-variant asthma.
  Wheezing is a high-pitched whistling sound produced by turbulent airflow through narrowed airways.

Other common symptoms include:

  Difficulty breathing
  Chest tightness
  Poor exercise endurance

Symptoms are often worse with exertion or during the night. Night cough is also common. Symptoms are also typically exacerbated by viral upper respiratory infections, and these viral symptoms can linger for weeks in children with asthma, whereas age-controlled counterparts tend to recover much sooner. Symptoms can also have a seasonal variation, which can be due to environmental allergies. Tobacco smoke commonly aggravates symptoms, and secondhand tobacco smoke is not only a risk factor for developing childhood asthma, but also complicates asthma control. Children with asthma often have a history of recurrent bronchitis or even a recurrent croup-like cough.

The physical exam in asthma is often completely normal. Occasionally, wheezing is present. In an asthma exacerbation, the respiratory rate increases, the heart rate increases, and children can look as if breathing is much more difficult. They may require accessory muscles to breath, and retractions of the chest wall adjacent to the ribs are common. Younger children may become lethargic and less interested in feeding. It is important to note that blood oxygen levels typically remain fairly normal even in the midst of a significant asthma exacerbation.

About The Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program receives the highest amount of National Institutes of Health funding among all U.S. children’s hospitals. In addition, its unique family-centered care and public service programs have brought the 527-bed hospital recognition as a leading advocate for children and adolescents.


John Ascenzi
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Children’s Hospital of Philadelphia

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