INTEGRATIVE PHARMACOGENOMICS OF LEUKOTRIENE INHIBITION IN ASTHMA

描述(申请人提供)：哮喘影响全球约3亿人，是美国儿童住院的主要原因。白三烯调节剂是唯一常见的口服哮喘药物，因此在患者中通常是首选的。然而，对白三烯调节剂的治疗反应是高度不同的，多达一半的患者是无反应的。药物遗传学提供了“个性化药物”的前景，即个体对治疗的反应将由他或她的基因构成来指导。然而，将这一承诺转化为临床领域的工作进展缓慢。包括表达微阵列和高通量基因分型平台在内的基因组技术的最新进展为推进这一过程提供了前所未有的机会；将表达数据与基因数据相结合已被证明是一种强大的方法学方法。该项目的主要目标是证明识别有助于白三烯修饰剂表达反应的基因变异可以导致快速发现与这些药物在哮喘中的临床反应相关的遗传标记。我们为实现这一目标制定了以下具体目标：1.参与纵向哮喘队列的400个亲子三人组中，超过550,000个单核苷酸多态(SNPs)已经完成了基因分型。微阵列表达实验将在白三烯修饰剂齐留通处理和不处理的情况下进行，这些细胞系来自400名哮喘先证者(来自亲子三人组的“孩子”)中的每个人的永生化B淋巴细胞系。2.将使用对齐留通的反应的表达差异作为主要结果变量进行全基因组相关性研究。表达数量性状基因座(EQTL)是那些与药物诱导的表达差异关联最大的SNP，将被识别。3.使用哮喘细胞确定的最显著的eQTL将使用DNA和之前完成的哮喘患者服用齐留通的临床试验的信息进行临床验证。4.与齐留通反应相关的eQTL也将在另外两个已完成的临床试验中进行测试，以供哮喘患者服用第二种类型的白三烯调节剂孟鲁司特进行进一步验证。这些发现可能最终导致对白三烯调节剂在哮喘中的反应的预后测试的形成。此外，通过将基因组表达与群体遗传学相结合，这种方法可能被推广到通过环境基因座快速识别其他药物遗传或基因。词库术语：哮喘、白三烯、药物遗传学、基因表达、微阵列、基因组学、药物基因组学、全基因组关联研究、临床研究。公共卫生相关性：该项目寻求确定与哮喘中白三烯途径阻断药物的给药所导致的基因表达特征最密切相关的遗传标记。通过证明这些标志物也与哮喘的临床反应相关，这些标志物最终可能被用来帮助预测哮喘患者对抗白三烯药物的治疗反应。由于哮喘仍然是美国儿童住院和缺课的主要原因，优化药物治疗有可能大幅降低与这种疾病相关的发病率和经济负担。

DESCRIPTION (provided by applicant): Asthma affects an estimated 300 million individuals worldwide and is the leading cause of childhood hospitalizations in the United States. Leukotriene modifiers are the only common orally-administered class of asthma medications and, thus, are generally preferred among patients. However, the treatment response to leukotriene modifiers is highly heterogeneous, with as many as one-half of all patients being non-responders. Pharmacogenetics provides the promise of "personalized medicine", whereby an individual's response to therapy will be guided by his or her genetic make-up. However, the translation of this promise to the clinical realm has been slow. Recent advances in genomic technologies including expression microarrays and highthroughput genotyping platforms offer an unprecedented opportunity to advance this process; combining expression data with genotype data has been shown to be a powerful methodologic approach. The major goal of this project is to demonstrate that identifying genetic variants contributing to the expression response to leukotriene modifiers can lead to rapid discovery of genetic markers associated with the clinical response with these medications in asthma. We have structured our specific aims to accomplish this goal as follows: 1. Genotyping has been completed on over 550,000 single nucleotide polymorphisms (SNPs) in 400 parent-child trios participating in a longitudinal asthma cohort. Microarray expression experiments will be performed with and without treatment with the leukotriene modifier, zileuton, in immortalized B-lymphocyte cell lines derived from each of the 400 asthmatic probands (the "child" from the parent-child trios). 2. Genome-wide association studies will be conducted using expression differences in response to zileuton as the primary outcome variable. Expression quantitative trait loci (eQTL), those SNPs with the greatest association with pharmacologically induced expression differences, will be identified. 3. The most salient of eQTLs identified using asthmatic cells will be tested for clinical validation using DNA and information from a previously completed clinical trial of asthmatics taking zileuton. 4. The eQTLs associated with zileuton response will also be tested for further validation using asthmatic subjects taking a second type of leukotriene modifier, montelukast, in two additional completed clinical trials. These findings may ultimately lead to the formation of a prognostic test for response to leukotriene modifiers in asthma. Additionally, by integrating genomic expression with population genetics, this approach may be generalizable to the rapid identification of other pharmacogenetic or gene by environment loci. Thesaurus Terms: Asthma, leukotriene, pharmacogenetics, gene expression, microarray, genomics, pharmacogenomics, genome-wide association study, clinical research. PUBLIC HEALTH RELEVANCE: This project seeks to identify genetic markers most closely associated with the genetic expression signature resulting from administration of medications that block the leukotriene pathway in asthma. By demonstrating that these markers also correlate with the clinical response in asthma, the markers may eventually be used to help predict therapeutic response to anti-leukotriene medications in asthma. Since asthma remains the leading cause of childhood hospitalizations and school absences in the United States, optimizing pharmacologic therapy has the potential to substantially decrease the morbidity and financial burden related to this disease.