Pharmacogenetics Network For Cardiovascular Risk Therapy

描述(申请人提供)：本次药物遗传学研究的目标 小组的目的是确定对个体间有贡献的常见基因变异 用于降低心血管疾病风险的药物的反应差异 (CVD)。该小组由一个多学科调查小组组成，其中包括 在脂蛋白代谢和血压调节方面的专业知识；基因组学和 相关计算方法；临床试验；人类遗传学和遗传学 流行病学；转基因小鼠模型，以及数据库管理和 生物统计学。在目前的研究中，选择的药物是阿托伐他汀，一种HMG 降低血脂水平的辅酶A还原酶抑制剂和ACE药物雷米普利 一种降低血压的抑制剂。候选基因是那些带有产物的基因 在这些药物的潜在靶点的代谢途径中。DNA序列 将在24名高加索人和24名高加索人中检测50个基因的变异 非洲裔美国人，两个顺序不同的民族 多样性。基于单核苷酸多态(SNPs)的模式， 将为两个种族群体和群体中的每个基因构建单倍型 将确定2-4个大多数人特有的SNP基因类型 每个基因中常见的单倍型，至少存在于10%的 人口。阿托伐他汀效应相关基因的单倍型(27个基因) 将在600人(每个种族300人)中确定谁将 每日服用10毫克，连续服用8周。人类免疫缺陷相关基因的单倍型 雷米普利效应(23个基因)将在600名个体(300名来自 每个民族)，每天服用10毫克，为期12周。 与脂蛋白和血压相关的表型的详细测量 将在两个不同的群体和协会中进行监管 将与各自的候选单倍型一起寻找。功能性 特定序列变体的效果将在适当的转基因中进行测试 老鼠模型。未来的研究将用样本证实积极的发现。 来自正在进行的阿托伐他汀和血管紧张素转换酶抑制剂的大型临床终点试验 心理治疗。数据将被传输到药物遗传学知识库，并 其他基因组数据库。这些发现将推进我们的根本 对特定基因及其变体在调节中的作用的理解 在心血管疾病发病机制和治疗中的重要生物学途径。

DESCRIPTION (provided by applicant): The goal of this Pharmacogenetics Research Group is to identify common gene variants that contribute to interindividual differences in response to drugs used to reduce risk for cardiovascular disease (CVD). The Group comprises a multidisciplinary team of investigators with expertise in lipoprotein metabolism and blood pressure regulation; genomics and related computational methodology; clinical trials; human genetics and genetic epidemiology; transgenic mouse models, and database management and biostatistics. For the present study, the drugs chosen are atorvastatin, an HMG CoA reductase inhibitor that lowers plasma lipid levels, and ramipril, an ACE inhibitor that lowers blood pressure. Candidate genes are those with products in metabolic pathways that are potential targets of these drugs. DNA sequence variations in 50 genes will be determined in 24 Caucasians and 24 African-Americans, two ethnic groups with differing degrees of sequence diversity. Based on patterns of single nucleotide polymorphisms (SNPs), haplotypes will be constructed for each gene in both ethnic groups, and groups of SNP genotypes will be identified that are characteristic for the 2-4 most common haplotypes in each gene, present in at least 10 percent of the population. Haplotypes for genes related to atorvastatin effects (27 genes) will be determined in 600 individuals (300 from each ethnic group) who will receive 10 mg/day of this drug for 8 weeks. Haplotypes for genes related to ramipril effects (23 genes) will be determined in 600 individuals (300 from each ethnic group) who will receive 10 mg/day of this drug for 12 weeks. Detailed measurements of phenotypes related to lipoprotein and blood pressure regulation will be performed in the two respective cohorts, and associations will be sought with each of the respective candidate haplotypes. Functional effects of specific sequence variants will be tested in appropriate transgenic mouse models. Future studies will corroborate positive findings using samples from large ongoing clinical endpoint trials of atorvastatin and ACE inhibitor therapy. Data will be transmitted to the Pharmacogenetics Knowledge Base and other genomic databases. The findings will advance our fundamental understanding of the roles of specific genes and their variants in modulating biologic pathways of importance in the pathogenesis and management of CVD.