Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
N Engl J Med. 2011 Sep 29;365(13):1173-83. doi: 10.1056/NEJMoa0911353. Epub 2011 Sep 26.
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.
哮喘治疗的反应具有广泛的个体间变异性，许多患者没有反应。我们假设全基因组关联研究将揭示吸入性糖皮质激素反应的新的药物遗传学决定因素。
我们分析了一小部分基于基于家系筛查算法选择的具有统计学意义的强大变体，这些变体来自 534290 个单核苷酸多态性（SNP），以确定吸入性糖皮质激素对肺功能的影响。发现了一个显著的药物遗传学相关性，我们对其功能影响进行了描述。
我们在 SNP rs37972 处确定了一个显著的药物遗传学相关性，在四个独立的共 935 人的人群中得到了复制（P=0.0007），该 SNP 映射到糖皮质激素诱导转录物 1 基因（GLCCI1），并与 rs37973 完全连锁不平衡（即完全相关）。rs37972 和 rs37973 均与 GLCCI1 表达的降低有关。在分离的细胞系统中，rs37973 变体与显著降低的荧光素酶报告基因活性有关。来自治疗试验的汇总数据表明，携带变体等位基因的受试者对吸入性糖皮质激素的肺功能反应降低（汇总数据 P=0.0007）。总体而言，携带 rs37973 突变等位基因的治疗受试者的用力呼气量 1 秒内的平均（±SE）增加仅约为携带野生型等位基因的类似治疗受试者的三分之一（3.2±1.6%比 9.4±1.1%），其不良反应的风险显著更高（比值比，2.36；95%置信区间，1.27 至 4.41），基因型占吸入性糖皮质激素反应变异性的约 6.6%。
功能性 GLCCI1 变体与哮喘患者对吸入性糖皮质激素的反应明显降低有关。
