A Step toward Personalized Asthma Treatment
Jeffrey M. Drazen, M.D.
Inhaled glucocorticoids are used every day by millions of patients with asthma. As with all asthma-controller treatments, there is marked patient-to-patient variability in the therapeutic response1; about one in three patients with asthma who use inhaled glucocorticoids may not benefit from this treatment. It would be advantageous if we could identify, in advance, patients who would respond to such treatment, but we have not been able to do so, despite major efforts during the past decade. In this issue of the Journal, Tantisira and colleagues appear to have made progress toward reaching this goal with the identification of a genetic variant associated with the response to inhaled glucocorticoids in the treatment of asthma.2
To identify this genetic variant, the group first used the clinical data and DNA resources from patients enrolled in the Childhood Asthma Management Program (CAMP), sponsored by the National Heart, Lung, and Blood Institute.3 Children 5 through 12 years of age who had asthma of moderate severity were enrolled in CAMP and were treated for 5 years with budesonide (an inhaled glucocorticoid), nedocromil sodium, or placebo. The frequent measurements of lung function and careful monitoring for asthma exacerbations resulted in a rich database of clinical information for use in the genetic studies. But what made the cohort most useful to these investigators was the availability of DNA from the children with asthma and from their parents — so-called DNA trios. Armed with one sample from an affected child and one sample from each of the child's parents, the investigators were able to use family-based statistics to identify 13 single-nucleotide–polymorphism (SNP) candidates from the hundreds of thousands of SNPs they had genotyped.4 The authors then tested these potential candidates in four replication populations and identified a variant in the glucocorticoid-induced transcript 1 gene (GLCCI1), rs37972, associated with a decrease in forced expiratory volume in 1 second (FEV1) in response to treatment with inhaled glucocorticoids. To offer additional reassurance that they had identified a causative SNP, the investigators provided data from isolated cell systems containing the pharmacogenetically identified SNP (and rs37973, which is in complete linkage disequilibrium with rs37972) to show that the presence of these sequence variants was associated with biologic changes that would be consistent with a decreased response to these agents.