INTEGRATIVE PHARMACOGENOMICS OF LEUKOTRIENE INHIBITION IN ASTHMA

描述（由申请人提供）：哮喘影响全球约3亿人，是美国儿童住院治疗的主要原因。白三烯调节剂是唯一常见的口服哮喘药物，因此，通常是患者的首选。然而，对白三烯修饰剂的治疗反应是高度异质性的，多达一半的患者无反应。药物遗传学提供了“个性化医疗”的希望，据此，个体对治疗的反应将由他或她的基因组成来指导。然而，将这一前景转化为临床领域的速度很慢。基因组技术的最新进展，包括表达微阵列和高通量基因分型平台，为推进这一进程提供了前所未有的机会；将表达数据与基因型数据相结合已被证明是一种强有力的方法。该项目的主要目标是证明，识别对白三烯修饰剂的表达反应有贡献的遗传变异，可以快速发现与哮喘患者对这些药物的临床反应相关的遗传标记。为实现这一目标，我们制定了以下具体目标：参与纵向哮喘队列的400对父母-儿童三人组已完成超过550,000个单核苷酸多态性（snp）的基因分型。微阵列表达实验将在使用白三烯修饰剂zileuton或不使用白三烯修饰剂的情况下进行，实验对象是来自400名哮喘先证者（亲子三人组中的“孩子”）的永生化b淋巴细胞系。2. 全基因组关联研究将使用对zileuton的表达差异作为主要结果变量。表达数量性状位点（eQTL），即与药理学诱导的表达差异关联最大的snp。3. 使用哮喘细胞鉴定的最显著的eqtl将使用DNA和先前完成的服用zileuton的哮喘患者临床试验的信息进行临床验证测试。4. 与zileuton反应相关的eqtl也将在另外两项已完成的临床试验中进行测试，以进一步验证使用第二种白三烯修饰剂孟鲁司特的哮喘受试者。这些发现可能最终导致哮喘患者对白三烯调节剂反应的预后测试的形成。此外，通过整合基因组表达与群体遗传学，这种方法可以推广到通过环境位点快速鉴定其他药物遗传学或基因。主题词：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：该项目旨在确定与哮喘中阻断白三烯途径的药物管理所产生的遗传表达特征最密切相关的遗传标记。通过证明这些标记物也与哮喘的临床反应相关，这些标记物可能最终用于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该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.