INTEGRATIVE PHARMACOGENOMICS OF LEUKOTRIENE INHIBITION IN ASTHMA

哮喘白三烯抑制的综合药物基因组学

• 批准号: 8243556
• 负责人: KELAN G TANTISIRA
• 金额: $ 72.51万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243556
• 关键词: Affect; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Asthma; B-Lymphocytes; Biological; Breathing; Cell Line; Cells; Child; Childhood; Childhood Asthma; Clinical; Clinical Research; Clinical Trials; Code; DNA; Data; Development; Disease; Environment; Enzymes; Gene Cluster; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Variation; Genome; Genomics; Genotype; Goals; Health; Hospitalization; Human; Individual; Individual Differences; Inflammation Mediators; Investigation; Lead; Leukotriene Antagonists; Leukotriene Production; Leukotrienes; Lipoxygenase Inhibitors; Measures; Mediating; Medicine; Methods; Microarray Analysis; Molecular Profiling; Morbidity - disease rate; Parents; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Play; Population; Population Genetics; Process; Quantitative Trait Loci; Research; Resources; Respiratory physiology; Role; Schools; Single Nucleotide Polymorphism; Site; Staging; Statistical Methods; Structure; Technology; Testing; Therapeutic; Thesauri; Translations; United States; Validation; Variant; Zileuton; base; bench to bedside; cohort; gene environment interaction; genetic variant; genome wide association study; inhibitor/antagonist; insight; interest; montelukast; novel; primary outcome; proband; prognostic; programs; research study; response; treatment response

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.

描述（由申请人提供）：哮喘影响全球估计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，因此通常是患者的首选。然而，对白三烯调节剂的治疗反应是高度异质性的，所有患者中有多达一半是无反应者。药物遗传学提供了“个性化医疗”的承诺，即个人对治疗的反应将由他或她的遗传组成指导。然而，将这一承诺转化为临床领域的速度一直很慢。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提供了一个前所未有的机会，推进这一进程，结合基因型数据的表达数据已被证明是一个强大的方法。该项目的主要目标是证明，识别有助于对白三烯修饰剂的表达反应的遗传变异，可以快速发现与这些药物治疗哮喘的临床反应相关的遗传标记。为了实现这一目标，我们制定了以下具体目标：1.在参与纵向哮喘队列的400个亲子三人组中，已经完成了超过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有和没有用白三烯修饰剂齐留通处理的情况下，在来自400个哮喘先证者中的每一个的永生化B淋巴细胞系中进行（来自父母-孩子三人组的“孩子”）。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关联研究。将鉴定表达数量性状基因座（eQTL），即与ESTs诱导的表达差异相关性最大的SNP。3.使用哮喘细胞鉴定的最突出的eQTL将使用来自先前完成的哮喘患者服用齐留通的临床试验的DNA和信息进行临床验证。4.与齐留通反应相关的eQTL也将在另外两项已完成的临床试验中使用服用第二种类型的白三烯调节剂孟鲁司特的哮喘受试者进行进一步验证。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检测。此外，通过将基因组表达与群体遗传学相结合，这种方法可以推广到其他药物遗传学或环境基因位点的快速鉴定。同义词词典术语：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：该项目旨在确定与哮喘中阻断白三烯途径的药物管理所产生的基因表达签名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，这些标记物最终可能用于帮助预测哮喘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，因此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。