GLCCI1 rs37973: a potential genetic predictor of therapeutic response to inhaled corticosteroids in Chinese chronic obstructive pulmonary disease patients.
GLCCI1 rs37973: a potential genetic predictor of therapeutic response to inhaled corticosteroids in Chinese chronic obstructive pulmonary disease patients.
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GLCCI1 rs37973：中国慢性阻塞性肺病患者吸入皮质类固醇治疗反应的潜在遗传预测因子
DOI：
10.1038/srep42552
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发表时间：
2017-02-10
影响因子：
4.6
通讯作者：
Xie J
中科院分区：
文献类型：
--
作者：
Lei Y;Gao Y;Chen J;Li M;Wu X;Ning Q;Zhao J;Xiong W;Xu Y;Xie J
吸入性皮质类固醇(ICSS)在慢性阻塞性肺疾病(COPD)中被广泛使用。然而，对ICSS治疗反应的预测因素知之甚少。探讨糖皮质激素诱导转录本1(GLCCI1)rs37973的变异是否与ICS疗效相关。纳入204例临床稳定的慢性阻塞性肺疾病患者，给予丙酸氟替卡松/沙美特罗联合雾化吸入(500/50微克，每日2次)治疗24周。我们对rs37973进行了基因分型，主要评估其对肺功能变化的影响。在体外，将部分患者分离的中性粒细胞与不同浓度的地塞米松(0，10−6M和10−4M)在有或没有香烟烟雾提取物的情况下孵育，然后用流式细胞仪检测细胞凋亡。治疗24周后，GG纯合子患者FEV1的改善程度明显低于AA(92.7±29.6mL；p 0.001)或AG(59.4±26.9mL；p 0.001)纯合子。在体外，地塞米松对GG纯合子对中性粒细胞凋亡的抑制作用较小，进一步证实了突变等位基因‘G’的存在可能与吸烟状态无关。Rs37973的GG基因型可能与中国COPD患者ICSS疗效降低有关。
Inhaled corticosteroids (ICSs) are widely prescribed in chronic obstructive pulmonary disease (COPD). However, little is known about predictors of ICSs therapeutic response. To investigate whether the variation in glucocorticoid-induced transcript 1 (GLCCI1) rs37973 is associated with ICS efficacy. A total of 204 clinically stable COPD patients were recruited and administered to inhaled fluticasone propionate/salmeterol combination (500/50 ug, twice daily) for 24 weeks. We genotyped the functional rs37973 and mainly assessed its effects on changes in lung function.In vitro, neutrophils isolated from parts of patients were incubated with various concentrations of dexamethasone (0, 10−6 M and 10−4 M) in the presence or absence of cigarette smoke extract, apoptosis was then assessed by flow cytometry. Patients with the homozygous GG genotype (increases of 15.3 ± 33.2 mL) had significantly poorer improvement in FEV1than those with the AA (92.7 ± 29.6 mL;p 0.001) or AG (59.4 ± 26.9 mL;p 0.001) genotypes after 24-week treatment.In vitro, dexamethasone had less inhibitory effect of neutrophil apoptosis on GG genotype, which further validated the presence of mutant allele ‘G’ might negatively affect glucocorticoid responsiveness irrespective of smoking status. The GG genotype of rs37973 may associated with decreased ICSs efficacy in Chinese COPD patients.