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Gene Variant Affects Response to Asthma Drugs

A genetic variant may explain why some people with asthma don’t respond well to inhaled corticosteroids, the most widely prescribed medicine for long-term asthma control. In the future, knowledge of such variants could help doctors develop more effective, personalized asthma treatments.

Asthma is a complex inflammatory disease that affects more than 22 million people nationwide. It causes narrowing of the airways in the lungs and leads to wheezing, coughing, chest tightness and trouble breathing. Many factors can influence how severely the disease affects people and how well they respond to treatments.

A poor response to inhaled corticosteroids often runs in families, so scientists have suspected that genetics plays a role. To learn more, a team of researchers led by Dr. Kelan G. Tantisira of Brigham and Women's Hospital carried out a genome-wide association study of children with asthma and their parents. The scientists searched for genetic variants linked to a poor response to inhaled corticosteroids. The study was funded by NIH’s National Heart, Lung and Blood Institute (NHLBI), National Human Genome Research Institute (NHGRI) and the NIH Pharmacogenomics Research Network, among others.

The investigators first ran a genome-wide scan of the DNA of 118 children with asthma and their parents. As reported in the September 26, 2011, online edition of the New England Journal of Medicine, the researchers uncovered a variant in the gene called glucocorticoid-induced transcript 1 (GLCCI1) that appeared to be associated with a poor response to inhaled corticosteroids.

The scientists verified this association in 935 additional children and adults with asthma who had enrolled in 4 independent studies. About 1 in 6 study participants had 2 copies of the GLCCI1 variant. Compared to those with 2 copies of the regular GLCCI1 gene, patients carrying 2 copies of the variant were more than twice as likely to respond poorly to inhaled corticosteroids. Those with a poor response had an average of one-third the level of lung improvement from inhaler treatment as those with 2 regular copies of the gene.

In laboratory cultures, the scientists saw changes caused by the GLCCI1 variant that might explain why it leads to a decreased response to inhaled corticosteroids. However, more studies will be needed to better understand how the variant operates in the lungs.

The researchers estimate that the GLCCI1 variant accounts for about 6.6% of the overall variation to inhaled corticosteroids between people. Other factors that are yet to be discovered doubtless influence a person’s response to these drugs. Also, because most of the study participants were white, the results may not be applicable to people of other ethnicities. More studies will be needed to explore whether GLCCI1 contributes to corticosteroid response in other ethnic groups.

“This finding helps to explain the genetic basis for the long-standing observation that some people do not respond well to what is a common asthma treatment,” says NHLBI Acting Director Dr. Susan Shurin. “The study illustrates the importance of research examining the relationship between genetic makeup and response to therapy for asthma, and underscores the need for personalized treatment for those who have it.”