Epidemiological, pharmacogenomic and clinical impact of catechol-O-methyltransferase on cardiovascular disease

儿茶酚-O-甲基转移酶对心血管疾病的流行病学、药物基因组学和临床影响

基本信息

批准号：
9017826
负责人：
Kathryn Tayo Hall
金额：
$ 15.63万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9017826
关键词：
Address Affect Ankle Aspirin Atherosclerosis Attenuated Award Bioinformatics Biological Models Biology Blood Platelets Blood Pressure Candidate Disease Gene Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Catechol Estrogens Catechol O-Methyltransferase Catecholamines Cause of Death Characteristics Clinical Clinical Research Clinical Trials Clinical Trials Design Complex Data Development Disease Drug Interactions Enzymes Epidemiologic Studies Epidemiology Epinephrine Evaluation Event Functional disorder Gene Expression Genes Genetic Genetic Crossing Over Genetic Polymorphism Genetic Variation Genome Genomics Genotype Glycosylated hemoglobin A Goals Health High Prevalence Incidence Individual Libraries Link Maps Mediating Molecular Norepinephrine P-Selectin Pathway Analysis Pathway interactions Pharmaceutical Preparations Pharmacogenomics Phase Phenotype Physiological Placebos Platelet Activation Preclinical Drug Evaluation Prevention Preventive treatment Public Health Randomized Research Research Personnel Research Proposals Resources Rest Risk Factors Role Sample Size Smooth Muscle Myocytes Specific qualifier value Systems Biology Testing Therapeutic Training Training Support Translational Research Translations Triglycerides United States Variant Vascular Smooth Muscle Woman Women&apos s Health abstracting cardiovascular disorder epidemiology cardiovascular disorder prevention cardiovascular disorder risk cardiovascular risk factor career development cohort coronary artery calcification drug metabolism epidemiologic data ethnic diversity genetic epidemiology genetic variant genome wide association study genomic data improved in vivo indexing insight intimal medial thickening novel strategies oxidant stress personalized medicine racial diversity randomized placebo controlled trial response sex small molecule success treatment response trial comparing

项目摘要

DESCRIPTION (provided by applicant): This award will support the training and career development of a junior investigator in cardiovascular epidemiology and pharmacogenomics, with special emphasis on the role of catechol-O-methyltransferase (COMT) in cardiovascular disease (CVD) and preventive treatment. Despite significant strides in prevention and management, CVD remains a leading cause of death in the United States. Pharmacogenomics, the study of how an individual's genome affects their treatment response, has expanded our understanding of the pathophysiology and treatment of CVD. However, gene-drug interactions have been difficult to assess in epidemiologic and clinical studies, in part because of the extraordinarily large sample sizes required for genome-wide association studies of these interactions and lack of strong candidate genes. COMT, which encodes a key enzyme in degradation of catecholamines including epinephrine, norepinephrine and catechol estrogen, is a strong candidate gene with plausible physiological links to both CVD and drug metabolism. COMT rs4680 is a well-studied and extremely common genetic polymorphism which results in a 3-4 fold reduction in enzymatic activity. The COMT genetic variant encoding the low-activity form of the enzyme, was associated with increased CVD risk and higher levels of triglycerides, systolic blood pressure and hemoglobin A1c in the Women's (Genome) Health Study (N=23,294). Interestingly over the 10 years of the study, women homozygous for the COMT low-activity genotype randomized to aspirin treatment had lower rates of CVD. Conversely, COMT high-activity homozygous women randomized to aspirin had higher CVD rates compared to placebo. Given the widespread use of aspirin for prevention of CVD, and the high prevalence of COMT rs4680 genetic variants, it is imperative that we understand the generalizability, mechanism and impact of the COMT locus itself and drugs that may share common molecular pathways and networks with it. This translational research proposal addresses these gaps by: 1) an epidemiologic study of COMT association with incidence of subclinical and clinical CVD in a multi-ethnic cohort; 2) using large-scale gene-expression and pharmacogenomic data to elucidate COMT molecular pathways and interacting drugs, and 3) conducting clinical studies to examine effects of these drugs on ex-vivo and in-vivo platelet function. As an emerging genetic locus with pleiotropic CVD and drug interaction effects, COMT is an excellent model system to probe the multiple molecular pathways and networks involved in cardiovascular function, disease and treatment and thus guide the development of novel strategies to attenuate CVD risk, and a promising example in which to develop personal expertise in cardiovascular epidemiology, systems biology, clinical trials, and other key career development milestones. (End of Abstract)

描述（由适用提供）：该奖项将支持心血管流行病学和药物基因组学初级研究者的培训和职业发展，并特别强调了儿茶酚-O-甲基转移酶（COMT）在心血管疾病（CVD）和预防治疗中的作用。尽管在预防和管理方面取得了长足的进步，但CVD仍然是美国的主要死亡原因。药物基因组学是关于个体基因组如何影响其治疗反应的研究，它扩大了我们对CVD的病理生理学和治疗的理解。然而，在流行病学和临床研究中很难评估基因 - 药物相互作用，部分原因是全基因组相互作用所需的样本量非常大，并且缺乏强大的候选基因。 COMT编码一个关键酶，用于降解儿茶酚胺在内的肾上腺素，去甲肾上腺素和雌激素，是一个强大的候选基因，具有与CVD和药物代谢的合理的物理联系。 COMT RS4680是一种研究良好且极为常见的遗传多态性，导致酶活性的3-4倍降低。在女性（基因组）健康研究中（n = 23,294）中，编码酶的低活性形式的COMT遗传变异与CVD风险增加和较高水平的甘油三酸酯，收缩压和血红蛋白A1C有关（n = 23,294）。有趣的是，在这项研究的10年中，与阿司匹林治疗随机分配的COMT低活性基因型的纯合女性的CVD发生率较低。相反，与安慰剂相比，COMT高活动性纯合妇女的CVD率更高。考虑到阿司匹林在预防CVD的宽度上以及COMT rs4680遗传变异的高流行率，我们必须了解COMT基因座本身的普遍性，机制和影响以及可能与之共享共同分子途径和网络的药物的普遍性，机制和影响。这项翻译的研究建议通过以下方式解决了以下差距：1）COMT与亚临床和临床CVD发生率相关的流行病学研究； 2）使用大规模的基因表达和药物基因组数据来阐明COMT分子途径和相互作用的药物，以及3）进行临床研究以检查这些药物对Ex-Vivo和体内血小板功能的影响。 As an emerging genetic locus with pleiotropic CVD and drug interaction effects, COMT is an excellent model system to probe the multiple molecular pathways and networks involved in cardiovascular function, disease and treatment and thus guide the development of novel strategies to attenuate CVD risk, and a promising example in which to develop personal expertise in cardiovascular epidemiology, systems biology, clinical trials, and other key career development milestones. （抽象的结尾）