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Rare Genetic Variants May Contribute to Severe Adverse Events in Asthma


Variants in a specific receptor gene appear to modulate therapeutic response in a small subset of patients who take long-acting ß-agonists.

Using predictive biomarkers, researchers have identified an at-risk, susceptible subpopulation of asthma patients who take long-acting ß-agonists (LABA), according to the results of a study that may eventually lead to personalized care.

Rare variants in the ß2-adrenergic receptor gene ADRB2 appear to modulate therapeutic responses to LABA therapy and contribute to rare, severe adverse events. Severe, adverse life-threatening events associated with LABA use have caused the FDA to review the safety of these drugs, resulting in a boxed warning and a mandatory safety study in more than 46,000 patients with asthma.

“This severe reaction only occurs in a very small percentage of people who have asthma, and we don’t know what makes these people different from those who do well on this therapy,” said Eugene Bleecker, MD, director of the Center for Genomics and Personalized Medicine Research at Wake Forest Baptist Medical Center.

Dr Bleecker and colleagues identified and evaluated 6 rare gene variants within the ß2-adrenergic receptor gene through the sequencing of DNA from blood samples of 191 non-Hispanic white, 197 African American, and 73 Puerto Rican asthma patients.

The researchers found that African American asthma patients had 5 rare variants, a far greater number compared with non-Hispanic white patients who only had 1 variant. The Puerto Rican patients had only 1 variant, which had previously only been identified in African Americans. This suggests that a higher frequency of rare genetic variants could account for the differences in responses to LABAs.

Then the researchers evaluated more than 1200 asthma patients and found that these rare variants significantly increased the risk of a hospital admission in the past year among asthma patients treated with a LABA. This association was not observed in those who were not treated with the drugs. In addition, they found that 2 variants significantly increased urgent outpatient visits and treatment with oral or injectable corticosteroids because of increased asthma symptoms in patients treated with an LABA.

Looking at data on asthma symptoms, the researchers found that non-Hispanic whites who had a rare variant were more than twice as likely to have uncontrolled symptoms during LABA therapy. This finding was replicated in a separate group of 516 non-Hispanic whites who were treated with LABAs at 12-month and 24-month follow-up visits. Non-Hispanic whites from both the primary and replication groups with this rare variant were more than twice as likely to experience uncontrolled, persistent symptoms during treatment with an LABA.

At the moment, the researchers do not recommend screening for these rare variants until further research validates their findings. However, genetic testing may be helpful for persons with severe asthma who are being treated with multiple therapies, including high-dose inhaled corticosteroids and LABAs, and are still uncontrolled and very symptomatic.

With additional research, they believe that there is the potential to identify genetic biomarkers that could predict the best treatment option for asthma patients, which is a goal of personalized medicine.

The researchers published their results in the March 2014 issue of The Lancet Respiratory Medicine.


Ortega VE, Hawkins GA, Moore WC, et al. Effect of rare variants in ADRB2 on risk of severe exacerbations and symptom control during long-acting β agonist treatment in a multiethnic asthma population: a genetic study. Lancet Respir Med. 2014;2:204-213.


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