Genetic association with response to glucocorticoid therapy in asthma

January 01, 0001

Genetic association with response to glucocorticoid therapy in asthma

The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. These US investigators hypothesized that a genomewide association study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids. They analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm from among 534,290 single-nucleotide polymorphisms (SNPs) to determine changes in lung function in response to inhaled glucocorticoids. A significant, replicated association was found, and they characterized its functional effects.

They found: "We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons, which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele. Overall, the meanincrease in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2% vs. 9.4%), and their risk of a poor response was significantly higher (odds ratio, 2.36), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability."

The authors concluded: "A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma."

Accounting for less than 7% of the variability in treatment response may not be enough to be clinically significant.

For the full abstract, click here.

N Engl J Med 365:1173-1183, 29 September 2011 © 2011 to the Massachusetts Medical Society
Genomewide Association between GLCCI1 and Response to Glucocorticoid Therapy in Asthma. Kelan G. Tantisira, Jessica Lasky-Su, Michishige Harada, et al. Correspondence to Dr. Tantisira: [email protected]

Category: R. Respiratory. Keywords: asthma, glucocorticoid therapy, genetic variant, GLCCI1, observational study, journal watch.
Synopsis edited by Dr Linda French, Toledo, Ohio. Posted on Global Family Doctor 7 October 2011

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