title: Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma.
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.
authors: Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, USA. rekgt@channing.harvard.edu
authors: Kelan G
authors: KG
authors: Tantisira
authors: Jessica
authors: J
authors: Lasky-Su
authors: Michishige
authors: M
authors: Harada
authors: Amy
authors: A
authors: Murphy
authors: Augusto A
authors: AA
authors: Litonjua
authors: Blanca E
authors: BE
authors: Himes
authors: Christoph
authors: C
authors: Lange
authors: Ross
authors: R
authors: Lazarus
authors: Jody
authors: J
authors: Sylvia
authors: Barbara
authors: B
authors: Klanderman
authors: Qing Ling
authors: QL
authors: Duan
authors: Weiliang
authors: W
authors: Qiu
authors: Tomomitsu
authors: T
authors: Hirota
authors: Fernando D
authors: FD
authors: Martinez
authors: David
authors: D
authors: Mauger
authors: Christine
authors: C
authors: Sorkness
authors: Stanley
authors: S
authors: Szefler
authors: Stephen C
authors: SC
authors: Lazarus
authors: Robert F
authors: RF
authors: Lemanske
authors: Stephen P
authors: SP
authors: Peters
authors: John J
authors: JJ
authors: Lima
authors: Yusuke
authors: Y
authors: Nakamura
authors: Mayumi
authors: M
authors: Tamari
authors: Scott T
authors: ST
authors: Weiss
mesh_terms: D000328:Adult; D000465:Algorithms; D001249:Asthma / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism
chemical_list: C561807:GLCCI1 protein, human; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid