Genomewide Association between GLCCI1 and Response to Glucocorticoid Therapy in Asthma
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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Genomewide Association between <i>GLCCI1</i> and Response to Glucocorticoid Therapy in Asthma
- Date Crossref
- 29/09/2011
- Éditeur
- Massachusetts Medical Society
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Brigham and Women's Hospital Pulmonary Division pays non établi dans la noticeÉtablissement de santé
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Harvard University pays non établi dans la noticeUniversité ou école supérieure
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University of Arizona Arizona Respiratory Center and Department of Pediatrics pays non établi dans la noticeUniversité ou école supérieure
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Arizona Science Center pays non établi dans la noticeOrganisation à but non lucratif
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Penn State Milton S. Hershey Medical Center pays non établi dans la noticeÉtablissement de santé
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University of Colorado Health Department of Pediatrics pays non établi dans la noticeÉtablissement de santé
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University of California Department of Medicine pays non établi dans la noticeUniversité ou école supérieure
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Wake Forest University Allergy and Immunologic Diseases pays non établi dans la noticeUniversité ou école supérieure
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Channing Laboratory pays non établi dans la noticeStructure de recherche
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Kanagawa pays non établi dans la noticeInstitution
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Harvard School of Public Health Brigham and Women's Hospital and Harvard Medical School pays non établi dans la noticeUniversité ou école supérieure
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Penn State Hershey College of Medicine pays non établi dans la noticeUniversité ou école supérieure
Pulmonary Division — Brigham and Women's Hospital, Harvard University et Arizona Respiratory Center and Department of Pediatrics — University of Arizona, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.