Genomewide Association between GLCCI1 and Response to Glucocorticoid Therapy in Asthma

Kelan G. Tantisira, M.D., Jessica Lasky-Su, Sc.D., Michishige Harada, Ph.D., Amy Murphy, Ph.D., Augusto A. Litonjua, M.D., Blanca E. Himes, Ph.D., Christoph Lange, Ph.D., Ross Lazarus, M.B., B.S., Jody Sylvia, B.S., Barbara Klanderman, Ph.D., Qing Ling Duan, Ph.D., Weiliang Qiu, Ph.D., Tomomitsu Hirota, Ph.D., Fernando D. Martinez, M.D., David Mauger, Ph.D., Christine Sorkness, Pharm.D., Stanley Szefler, M.D., Stephen C. Lazarus, M.D., Robert F. Lemanske, Jr., M.D., Stephen P. Peters, M.D., Ph.D., John J. Lima, Pharm.D., Yusuke Nakamura, M.D., Ph.D., Mayumi Tamari, M.D., Ph.D., and Scott T. Weiss, M.D.

N Engl J Med 2011; 365:1173-1183September 29, 2011

Comments open through October 5, 2011

Abstract
Article
References
Citing Articles (1)
Comments: Background
The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. We hypothesized that a genomewide association study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids.
Full Text of Background...
Methods
We 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 we characterized its functional effects.
Full Text of Methods...
Results
We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P=0.0007), 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 (P=0.0007 for pooled data). Overall, the mean (±SE) increase 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±1.6% vs. 9.4±1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability.
Full Text of Results...
Conclusions
A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00000575.)
Full Text of Discussion...
Read the Full Article...
Media in This Article
Figure 1Study Design.
Figure 2Changes in Lung Function with Therapy According to rs37972 Genotype.
Article Activity
1 article has cited this article; Asthma is a complex genetic syndrome that affects 300 million persons worldwide.1 The response to treatment is also genetically complex and is characterized by high intraindividual repeatability2 and high interindividual variability,3 with up to 40% of patients with asthma having no response to therapy.; Inhaled glucocorticoids are the most widely prescribed medications for controlling asthma. Levels of endogenous glucocorticoids are heritable and vary, both at baseline and in response to environmental perturbation.4-6 Moreover, studies in families with conditions other than asthma have shown both familial segregation and heritability in responses to glucocorticoid medications.7,8 Given the heritability within the therapeutic class of glucocorticoids, as well as the high degrees of between-patient variability and within-patient repeatability in the response to inhaled glucocorticoids for the treatment of asthma, it is likely that this response has a genetic basis.; To date, pharmacogenetic investigations in asthma have focused on candidate genes.9-13 A powerful family-based screening algorithm14 for genomewide association studies has identified novel genetic loci that contribute to obesity15,16 and Alzheimer's disease.17 The algorithm uses parental genotype information to rank single-nucleotide polymorphisms (SNPs) that have the greatest potential power for association. A small subset of statistically powerful SNPs can then be tested in the probands with the use of the family-based association test (FBAT).18 Identifying markers in this fashion limits the potential for false-positive associations and increases the likelihood of replication in subsequent studies.; We hypothesized that a genomewide association study would identify novel variants associated with the response to inhaled glucocorticoids for asthma. We tested this hypothesis with the use of the family-based screening algorithm in subjects randomly assigned to inhaled glucocorticoids in the Childhood Asthma Management Program (CAMP).19,20 Through screening, we identified SNPs that offered the greatest power for a replicable association with the longitudinal response to inhaled glucocorticoids, measured as a change in forced expiratory volume in 1 second (FEV₁). After screening, we tested the association of the highest-powered SNPs in four additional, independent populations drawn from clinical trials involving subjects with asthma