Effect of Gly16Arg Polymorphism in ADRB2 Gene on Asthma Control in Children Receiving Long Acting Beta Agonists

Asthma is the most common chronic disease of childhood affecting 6.2 million children between 2 and 18 years of age, and is the most common cause of school absenteeism due to chronic disease. African American children are 3 to 4 times more likely to be hospitalized for asthma and 4 to 6 times more likely to die from the disease compared to European Americans. The economic burden in this country from asthma is enormous, exceeding $16 billion in 2004. Though there is no cure for asthma, several drugs are available that have been shown to be generally safe and effective in controlling symptoms. Beta 2 agonists are the most commonly used asthma drugs. When inhaled these drugs relax cells in the lungs, which helps patients with asthma breath easier. Two types of beta agonists in use are short-acting beta agonists (SABA) and long-acting beta agonists (LABA). SABA, like albuterol, are used to provide quick relief of chest tightening which help patients to breathe easier. Long-acting beta agonists (LABA) also help patients breathe easier and for a longer period of time. Continued SABA use (for example, inhale albuterol 3 or 4 times a day) is not recommended, and continued LABA use is recommended only if used together with inhaled corticosteroids (ICS). ICS are the most commonly used drug used in asthma that protects against inflammation in the lung. Studies over the past 50 years suggest that continued use of SABA, LABA, and the combination of ICS+LABA may worsen asthma in some patients by reducing the effect of the beta agonists, increasing the rate of asthma attacks, decreasing the ability of the lung to work efficiently, and death. Recent studies suggest asthma worsening by continued beta agonist use occurs in individuals with a certain genotype. Genotype refers to form of the protein, called the beta2 adrenergic receptor (b2AR), in the lung that beta agonists work on. Because of differences in genetic make up, there are different forms of the b2AR. One form is called the Arg16 genotype the other form is called the Gly16 genotype. Compared to Gly16 genotypes, patients with asthma genotyped as Arg16 appear to be more susceptible to asthma worsening that has been associated with continued use SABA, LABA or ICS+LABA. Most of the studies of the influence of genotype on asthma worsening associated with beta agonist use have been performed in adults. The results of a small number of studies suggest children are more susceptible to asthma worsening from chronic beta agonist use compared to adults, and that children with the Arg16 genotype are more susceptible to having asthma attacks than children with the Gly16 genotype. Some evidence suggest that children with asthma should not be treated with ICS+LABA, yet since 2000, the rate at which children with asthma are switched from ICS therapy alone to ICS+LABA has increased significantly. The major question posed by the proposed study is: Does treatment with ICS+LABA compared to ICS alone cause worsening of asthma in children with asthma genotyped as Arg16 homozygotes but not in Gly16 homozygotes? The specific aim of the project is to evaluate the safety of ICS+LABA in children with asthma when separated according genotype. Children with asthma will be screened, be assented and their care taker (parent, for example) consented. A sample of saliva will be collected from which genetic material (DNA) will be collected for the purpose of genotyping. A total of 90 European and African American children, 45 Arg16 and 45 Gly16 genotypes, will be treated for 16 weeks. Half of each genotype will be randomly assigned to receive ICS alone for 16 weeks the other half will receive ICS+LABA. At the end of 16 weeks, those starting with ICS will be then receive ICS+LABA while those who received ICS+LABA first will then take ICS alone. Before and once a month during treatment, each participant will visit the clinic to undergo tests that will assess lung function, how well asthma is being controlled, level of inflammation and quality of life. The results of our study are expected to have a major impact on the way children with asthma are being treated with drugs. If the results of our study show that Arg16 genotypes have worse asthma when they are taking ICS+LABA compared to ICS alone we will conclude that the safety of combination in children is questionable and should be tested in a larger population of children to determine if this popular combination should be used in children with asthma. If the results show that the combination in both genotypes does not worsen asthma compared to ICS treatment, we will conclude that the combination is safe to use in children, at least for 16 weeks.