Pharmacogenomics and Risk of Cardiovascular Disease

药物基因组学和心血管疾病的风险

• 批准号: 7676698
• 负责人: RONALD M KRAUSS
• 金额: $ 218.71万
• 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/7676698
• 关键词: African American; Age; Apolipoproteins B; Apoproteins; C-reactive protein; CCL18 gene; Candidate Disease Gene; Cardiology; Cardiovascular Diseases; Cardiovascular system; Caucasians; Caucasoid Race; Cholesterol; Clinic; Clinical; Clinical Pharmacology; Clinical Trials; Collaborations; DNA; DNA Library; DNA Resequencing; Data; Drug Kinetics; Elderly; Epidemiology; Ethnic group; Gene Frequency; Genes; Genetic; Genetic Variation; Genomics; Genotype; Grant; Haplotypes; Heart; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Individual; Inflammation; Inflammatory; Informatics; Interdisciplinary Study; Jupiter; LDL Cholesterol Lipoproteins; Laboratories; Lipids; Lipoproteins; Low-Density Lipoproteins; Measurement; Measures; Medicine; Minor; Muscle; Myopathy; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Phenotype; Placebos; Plasma; Population; Population Study; Pravastatin; Prospective Studies; Research Project Grants; Risk; Sampling; Simvastatin; Single Nucleotide Polymorphism; Sterols; Stratification; Study Subject; Testing; Toxic effect; Triglycerides; Variant; atorvastatin; base; campesterol; cardiovascular disorder risk; cardiovascular risk factor; cholesterol absorption; clinical phenotype; clinical practice; clinically significant; cohort; density; design; genetic association; genome wide association study; genome-wide; high risk; indexing; inflammatory marker; lathosterol; patient population; prevent; programs; response; rosuvastatin; sex

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）：本资助的总体目标是定义和确认基因对他汀类药物治疗临床反应的巨大个体差异的贡献。多学科研究团队在基因组学、统计遗传学和信息学、临床药理学和心脏病学、心血管危险因素的实验室测量和流行病学方面具有专长。在序贯设计中，我们将使用来自总共10,000名接受各种他汀类药物治疗的受试者的样本，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、胆固醇吸收和合成标记物以及炎症标记物hs-CRP。对1000名来自辛伐他汀或普伐他汀试验的高加索受试者的初步分析将基于25万个全基因组snp的小组（Aim 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，验证性分析将产生1100个snp，这些snp与高加索人和非裔美国人LDL胆固醇和其他表型的他汀类药物反应变异最一致。此外，全基因组SNP面板以及候选基因SNP将用于在150例与300例匹配对照中识别与他汀类药物相关的肌病相关的SNP。对目标2和目标3中与他汀类药物诱导的低密度脂蛋白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48名白种人和48名非裔美国人中确定等位基因变异，这些等位基因随机选择自这些表型分布中最高和最低的5%（目标4）。最后，将测试这些snp与实验室表型和临床心血管结果的关系（目的5）。该计划提出了一种综合的方法来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临床有意义的反应性变化的影响。

项目成果

Ion mobility analysis of lipoprotein subfractions identifies three independent axes of cardiovascular risk.

脂蛋白亚构件的离子迁移率分析标识了三个独立的心血管风险轴。

• DOI: 10.1161/atvbaha.109.190405
• 发表时间: 2009-11
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Musunuru K;Orho-Melander M;Caulfield MP;Li S;Salameh WA;Reitz RE;Berglund G;Hedblad B;Engström G;Williams PT;Kathiresan S;Melander O;Krauss RM
• 通讯作者: Krauss RM

Analysis of polymorphisms in the 3' untranslated region of the LDL receptor gene and their effect on plasma cholesterol levels and drug response.

• DOI: 10.3892/ijmm.21.3.345
• 发表时间: 2008-03
• 期刊: International journal of molecular medicine
• 影响因子: 5.4
• 作者: Wei Chen-;Shukui Wang;Yuling Ma;Yue Zhou;Haiyan Liu;P. Strnad;F. Kraemer;R. Krauss;Jingwen Liu

The role of HMGCR alternative splicing in statin efficacy.

• DOI: 10.1016/j.tcm.2009.10.003
• 发表时间: 2009-07
• 期刊: TRENDS IN CARDIOVASCULAR MEDICINE
• 影响因子: 9.3
• 作者: Medina, Marisa Wong;Krauss, Ronald M.
• 通讯作者: Krauss, Ronald M.

Integrative modeling of eQTLs and cis-regulatory elements suggests mechanisms underlying cell type specificity of eQTLs.

• DOI: 10.1371/journal.pgen.1003649
• 发表时间: 2013
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Brown CD;Mangravite LM;Engelhardt BE
• 通讯作者: Engelhardt BE

Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2.

• DOI: 10.1093/hmg/ddab279
• 发表时间: 2022-03-21
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Pott J;Gådin JR;Theusch E;Kleber ME;Delgado GE;Kirsten H;Hauck SM;Burkhardt R;Scharnagl H;Krauss RM;Loeffler M;März W;Thiery J;Silveira A;Van't Hooft FM;Scholz M
• 通讯作者: Scholz M