Pharmacogenomics and Risk of Cardiovascular Disease

药物基因组学和心血管疾病的风险

• 批准号: 7485102
• 负责人: RONALD M KRAUSS
• 金额: $ 285.05万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485102
• 关键词: Address; African American; Age; American; Apolipoproteins B; Apoproteins; Arts; Atherosclerosis; Biological Markers; C-reactive protein; CCL18 gene; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Caucasians; Caucasoid Race; Cholesterol; Class; Clinic; Clinical; Clinical Informatics; Clinical Markers; Clinical Trials; Cohort Studies; Collaborations; Controlled Clinical Trials; Coronary heart disease; DNA; DNA Library; DNA Resequencing; Data; Development; Disease; Disease Outcome; Drug Kinetics; Drug toxicity; Elderly; End Point; Enzymes; Epidemiology; Ethnic group; Functional disorder; Funding; Gene Frequency; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Variation; Genome; Genomics; Genotype; Grant; Haplotypes; Heart; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hydroxymethylglutaryl-CoA reductase; Incidence; Individual; Individual Differences; Inflammation; Inflammatory; Interdisciplinary Study; Jupiter; Kidney; Knowledge; LDL Cholesterol Lipoproteins; Laboratories; Link; Lipids; Lipoproteins; Low-Density Lipoproteins; Measurement; Measures; Mediator of activation protein; Medical; Medication Management; Medicine; Metabolism; Minor; Modeling; Muscle; Myopathy; Nervous system structure; Numbers; Outcome; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Phenotype; Physiology; Placebos; Plasma; Population; Population Study; Pravastatin; Predisposition; Principal Investigator; Process; Prospective Studies; Public Health; Range; Rate; Recommendation; Recurrence; Reproducibility; Research Personnel; Research Project Grants; Risk; Risk Factors; Risk Reduction; Sampling; Simvastatin; Single Nucleotide Polymorphism; Standards of Weights and Measures; Sterols; Stratification; Stroke; Study Subject; Sum; Testing; Therapeutic; Tissues; Toxic effect; Triglycerides; Variant; atorvastatin; base; bone; campesterol; cardiovascular disorder risk; cardiovascular risk factor; cholesterol absorption; clinical phenotype; clinically significant; cohort; day; density; design; genetic association; genetic variant; genome wide association study; genotyping technology; heart pharmacology; indexing; insight; lathosterol; novel; prevent; programs; response; rosuvastatin; sex; success

DESCRIPTION (provided by applicant): The overall objective of this grant is to both define and confirm the genetic contribution to the large inter-individual variability in clinical response to treatment with statin drugs. The multidisciplinary research team has expertise in genomics, statistical genetics and informatics, clinical pharmacology and cardiology, laboratory measurements of cardiovascular risk factors, and epidemiology. In a sequential design, using samples from a total of 10,000 subjects treated with various statins, we will use a genome wide association approach to identify SNPs (single nucleotide polymorphisms) that are associated with laboratory measurements of statin response, including LDL and HDL subfractions, markers of cholesterol absorption and synthesis, and the inflammatory marker hs-CRP. Initial analyses in 1,000 Caucasian subjects from trials of simvastatin or pravastatin will be based on a panel of 250,000 genome-wide SNPs (Aim 1). Confirmatory analyses in cohorts treated with rosuvastatin (Aim 2) and atorvastatin (Aim 3) will yield a panel of 1,100 SNPs most consistently associated with variation in statin response of LDL cholesterol and other phenotypes in Caucasians and African-Americans. In addition, the genome-wide SNP panel along with candidate gene SNPs will be used to identify those associated with statin-related myopathy in 150 cases vs. 300 matched controls. Genomic resequencing of the 50 genes most strongly associated in Aims 2 and 3 with statininduced reductions in LDL cholesterol and other informative phenotypes will identify allelic variants in a total of 48 Caucasians and 48 African-American randomly selected from the highest and lowest 5% of the distributions of these phenotypes in the respective ethnic groups (Aim 4). Finally, these SNPs will be tested for associations with both laboratory phenotypes and clinical cardiovascular outcomes (Aim 5). This program presents a comprehensive approach for determining effects of specific genotypes on clinically meaningful variations in responsiveness to a class of drugs widely used to prevent cardiovascular disease.

描述（由申请人提供）：该资助的总体目标是定义和确认他汀类药物治疗临床反应中个体间差异的遗传贡献。该多学科研究团队拥有基因组学、统计遗传学和信息学、临床药理学和心脏病学、心血管风险因素的实验室测量和流行病学方面的专业知识。在序贯设计中，使用来自接受各种他汀类药物治疗的总计10，000名受试者的样本，我们将使用全基因组关联方法来鉴定与他汀类药物反应的实验室测量相关的SNP（单核苷酸多态性），包括LDL和HDL亚组分、胆固醇吸收和合成的标志物以及炎症标志物hs-CRP。来自辛伐他汀或普伐他汀试验的1,000名白人受试者的初步分析将基于一组250,000个全基因组SNP（目标1）。在接受瑞舒伐他汀（Aim 2）和阿托伐他汀（Aim 3）治疗的队列中进行的验证性分析将产生一组1，100个SNP，这些SNP与高加索人和非洲裔美国人中LDL胆固醇和其他表型的他汀类药物应答变异最一致相关。此外，全基因组SNP面板沿着候选基因SNP将用于在150例病例与300例匹配对照中鉴定与他汀类药物相关肌病相关的SNP。对目标2和3中与他汀类药物诱导的LDL胆固醇降低和其他信息表型最密切相关的50个基因进行基因组重测序，将在从相应种族组中这些表型分布的最高和最低5%中随机选择的总共48名高加索人和48名非洲裔美国人中鉴定等位基因变体（目标4）。最后，将测试这些SNP与实验室表型和临床心血管结局的相关性（目的5）。该计划提出了一种全面的方法，用于确定特定基因型对广泛用于预防心血管疾病的一类药物的反应性的临床有意义的变化的影响。