GLCCI1 rs37973: A potential genetic predictor of therapeutic response to inhaled corticosteroids in Chinese asthma patients

Abstract

Glucocorticoids are the primary anti-inflammatory therapy for asthma, but their effects are characterized by some interindividual variability that might have a genetic basis.We aimed to determine the relationship between pulmonary function change and the variant of the glucocorticoid-induced transcript 1 (GLCCI1) gene in patients with asthma receiving long-term ICS treatment, the association of GLCCI1 genotypes and the level of GLCCI1 expression and cytokines production.A total of 418 patients with asthma, including 25 individuals from 11 families with a history of asthma, were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1 on changes in lung function in response to inhaled glucocorticoids were assessed. The expression levels of GLCCI1 mRNA and cytokines were also measured.The SNP rs37973 in GLCCI1 was independently associated with changes in forced expiratory volume at one second (FEV1) and FEV1%pred. Individuals homozygous for the wild-type allele who had a percent FEV1 change greater than 5% were more common than individuals homozygous for the rare allele. When patients were stratified according to genotype, GLCCI1 expression was enhanced upon administration of low-dose dexamethasone among patients with the rs37973 A allele; however, GG homozygotes required high-dose dexamethasone to achieve enhanced GLCCI1 expression. Furthermore, the levels of some cytokines were significantly reduced after glucocorticoid treatment in individuals with the AA and AG genotypes.The genetic variant rs37973 in GLCCI1 is associated with poorer clinical therapeutic response to inhaled glucocorticoids in a Chinese asthma population.

Figure 1

Association of rs37973 genotypes and changes in lung function after 24 weeks of inhaled corticosteroid therapy in 418 asthma patients. (A) The association between the rs37973 polymorphism and change in FEV₁. (B) The association between the rs37973 polymorphism and change in FEV₁ (% of predicted); ^∗P < .05. FEV₁ = forced expiratory volume in one second.

Figure 2

The distribution of FEV₁ changes stratified by GLCCI1 rs37973 genotype in 418 patients with asthma after inhaled corticosteroid therapy.

Figure 3

Changes in lung function stratified by genotype after 24 weeks of inhaled corticosteroid therapy in 25 subjects from 11 families with a history of asthma. (A) The association between the rs37973 polymorphism and change in FEV₁. (B) The association between the rs37973 polymorphism and change in FEV₁ (% of predicted); ^∗P < .05. FEV₁ = forced expiratory volume in one second.

Figure 4

The expression of GLCCI1 mRNA induced by dexamethasone (DEX) in vitro mononuclear cells. (A) The expression of GLCCI1 mRNA stratified by the rs37973 genotype induced by 10⁻⁷ M dexamethasone with or without asthmatic serum (AS); (B) Elevated dexamethasone concentrations increased the expression of GLCCI1 in patients with the GG genotype (10⁻⁷ M vs. 10⁻⁶ M); ∗∗ P < .01.

Figure 5

Cytokine production stimulated by 10⁻⁷ M dexamethasone (DEX) with or without asthmatic serum (AS). The concentrations of (A) IL-6, (B) IL-8, (C) IL-10 and (D) IL-13 stratified by GLCCI1 rs37973 genotype after cultured for 24 hours with dexamethasone. ^∗∗P < .01; ^∗∗∗P < .001. AS = asthmatic serum, DX = dexamethasone.