Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma.
Pharmacodynamic genome-wide association study identifies new responsive loci for glucocorticoid intervention in asthma.
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DOI：
10.1038/tpj.2014.83
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Wu R
中科院分区：
文献类型：
--
作者：
Wang Y;Tong C;Wang Z;Wang Z;Mauger D;Tantisira KG;Israel E;Szefler SJ;Chinchilli VM;Boushey HA;Lazarus SC;Lemanske RF;Wu R
哮喘是一种发病率很高的慢性肺部疾病。如果实施患者对药物反应的遗传变异性，可以使这种疾病的治疗干预更加有效。然而，哮喘干预反应的遗传结构的清晰图像仍然难以捉摸。我们进行了一项全基因组关联研究（GWAS），以确定哮喘的药物反应相关基因，其中对120名吸入多剂量糖皮质激素的随机参与者进行了909，622个SNP的基因分型。通过整合药物反应的药效学特性，我们实施了一个机制模型来分析GWAS数据，增强了对哮喘干预的遗传结构的推断范围。我们的药效学模型观察到对吸入糖皮质激素的剂量依赖性反应（以%FEV1测量）与5个位点（p = 5.315 × 10−7至3.924 × 10−9）之间的全基因组显著性相关，其中许多位点映射到与肺功能和哮喘风险相关的代谢基因。检测到的所有显着SNP均表明隐性效应，其中突变等位基因的纯合子导致%FEV 1的变异性。在另外三项独立的GWAS研究中，显著的相关性得到了很好的复制。将这三项试验汇总在一起，两个SNP，chr6 rs6924808和chr11 rs1353649，显示出增加的显著性水平（p = 6.661 ×10−16和5.670×10−11）。我们的研究揭示了哮喘干预的药物基因组学控制的一般情况。所获得的结果有助于根据个体患者的基因组成为他们定制治疗哮喘的最佳剂量。
Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients’ response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909,622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (p = 5.315 × 10−7 to 3.924 × 10−9), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (p = 6.661 ×10−16 and 5.670×10−11). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.
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影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1164/rccm.2105013
发表时间：
2002-05-15
影响因子：
24.7
作者：
Martin, RJ;Szefler, SJ;Sorkness, CA
通讯作者：
Sorkness, CA