Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma.
Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma.
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DOI：
10.1056/nejmoa0911353
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发表时间：
2011-09-29
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影响因子：
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通讯作者：
Weiss ST
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作者：
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 FD;Mauger D;Sorkness C;Szefler S;Lazarus SC;Lemanske RF Jr;Peters SP;Lima JJ;Nakamura Y;Tamari M;Weiss ST
对哮喘治疗的反应具有广泛的个体差异，有相当数量的患者没有反应。我们假设全基因组关联研究将揭示吸入糖皮质激素反应的新药理学决定因素。我们分析了基于基于家族的筛选算法从534,290个单核苷酸多态性（snp）中选择的少量统计上强大的变异，以确定吸入糖皮质激素后肺功能的变化。我们发现了一个显著的、重复的关联，并描述了它的功能效应。我们发现SNP rs37972存在显著的药理学关联，在4个独立人群中共935人中重复（P = 0.0007），该关联定位于糖皮质激素诱导的转录物1基因（GLCCI1），并且与rs37973处于完全连锁不平衡（即完全相关）。rs37972和rs37973都与GLCCI1表达的减少有关。在分离的细胞系统中，rs37973变异与显著降低的荧光素酶报告活性相关。来自治疗试验的汇总数据表明，携带变异等位基因的受试者吸入糖皮质激素后肺功能降低（汇总数据P = 0.0007）。总体而言，rs37973突变等位基因纯合子治疗组1秒内用力呼气量的平均（±SE）增加仅为野生型等位基因纯合子治疗组的三分之一左右（3.2±1.6% vs. 9.4±1.1%），其不良反应的风险显著更高(优势比，2.36；95%可信区间为1.27 ~ 4.41)，基因型约占吸入糖皮质激素总体反应变异性的6.6%。功能性GLCCI1变异与哮喘患者吸入糖皮质激素反应的显著降低有关。（由美国国立卫生研究院和其他机构资助；ClinicalTrials.gov编号，NCT00000575。）
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. 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. 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. 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.)