Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma

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

Research output: Contribution to journalArticle

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Abstract

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. 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. 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. 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.)

Original languageEnglish (US)
Pages (from-to)1173-1183
Number of pages11
JournalNew England Journal of Medicine
Volume365
Issue number13
DOIs
StatePublished - Sep 29 2011

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Glucocorticoids
Asthma
Genes
Pharmacogenetics
Alleles
Therapeutics
Single Nucleotide Polymorphism
Lung
Linkage Disequilibrium
Forced Expiratory Volume
National Institutes of Health (U.S.)
Luciferases
Odds Ratio
Genotype
Confidence Intervals
Gene Expression
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Tantisira, K. G., Lasky-Su, J., Harada, M., Murphy, A., Litonjua, A. A., Himes, B. E., ... Weiss, S. T. (2011). Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. New England Journal of Medicine, 365(13), 1173-1183. https://doi.org/10.1056/NEJMoa0911353

Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. / Tantisira, Kelan G.; Lasky-Su, Jessica; Harada, Michishige; Murphy, Amy; Litonjua, Augusto A.; Himes, Blanca E.; Lange, Christoph; Lazarus, Ross; Sylvia, Jody; Klanderman, Barbara; Duan, Qing Ling; Qiu, Weiliang; Hirota, Tomomitsu; Martinez, Fernando; Mauger, David; Sorkness, Christine; Szefler, Stanley; Lazarus, Stephen C.; Lemanske, Robert F.; Peters, Stephen P.; Lima, John J.; Nakamura, Yusuke; Tamari, Mayumi; Weiss, Scott T.

In: New England Journal of Medicine, Vol. 365, No. 13, 29.09.2011, p. 1173-1183.

Research output: Contribution to journalArticle

Tantisira, KG, Lasky-Su, J, Harada, M, Murphy, A, Litonjua, AA, Himes, BE, Lange, C, Lazarus, R, Sylvia, J, Klanderman, B, Duan, QL, Qiu, W, Hirota, T, Martinez, F, Mauger, D, Sorkness, C, Szefler, S, Lazarus, SC, Lemanske, RF, Peters, SP, Lima, JJ, Nakamura, Y, Tamari, M & Weiss, ST 2011, 'Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma', New England Journal of Medicine, vol. 365, no. 13, pp. 1173-1183. https://doi.org/10.1056/NEJMoa0911353
Tantisira KG, Lasky-Su J, Harada M, Murphy A, Litonjua AA, Himes BE et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. New England Journal of Medicine. 2011 Sep 29;365(13):1173-1183. https://doi.org/10.1056/NEJMoa0911353
Tantisira, Kelan G. ; Lasky-Su, Jessica ; Harada, Michishige ; Murphy, Amy ; Litonjua, Augusto A. ; Himes, Blanca E. ; Lange, Christoph ; Lazarus, Ross ; Sylvia, Jody ; Klanderman, Barbara ; Duan, Qing Ling ; Qiu, Weiliang ; Hirota, Tomomitsu ; Martinez, Fernando ; Mauger, David ; Sorkness, Christine ; Szefler, Stanley ; Lazarus, Stephen C. ; Lemanske, Robert F. ; Peters, Stephen P. ; Lima, John J. ; Nakamura, Yusuke ; Tamari, Mayumi ; Weiss, Scott T. / Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. In: New England Journal of Medicine. 2011 ; Vol. 365, No. 13. pp. 1173-1183.
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AU - Tantisira, Kelan G.

AU - Lasky-Su, Jessica

AU - Harada, Michishige

AU - Murphy, Amy

AU - Litonjua, Augusto A.

AU - Himes, Blanca E.

AU - Lange, Christoph

AU - Lazarus, Ross

AU - Sylvia, Jody

AU - Klanderman, Barbara

AU - Duan, Qing Ling

AU - Qiu, Weiliang

AU - Hirota, Tomomitsu

AU - Martinez, Fernando

AU - Mauger, David

AU - Sorkness, Christine

AU - Szefler, Stanley

AU - Lazarus, Stephen C.

AU - Lemanske, Robert F.

AU - Peters, Stephen P.

AU - Lima, John J.

AU - Nakamura, Yusuke

AU - Tamari, Mayumi

AU - Weiss, Scott T.

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N2 - 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. 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. 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. 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.)

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