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

• 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
• 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' 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

 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(申请人提供)：该奖项将支持心血管流行病学和药物基因组学初级研究员的培训和职业发展，特别强调儿茶酚-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重大进展，但心血管疾病仍然是美国的主要死亡原因。药物基因组学是研究一个人的基因组如何影响他们的治疗反应的，它扩大了我们对心血管疾病的病理生理和治疗的理解。然而，在流行病学和临床研究中，基因-药物相互作用很难评估，部分原因是这些相互作用的全基因组关联研究需要非常大的样本量，并且缺乏强有力的候选基因。COMT编码包括肾上腺素、去甲肾上腺素和儿茶酚雌激素在内的儿茶酚胺降解的关键酶，是一个与心血管疾病和药物代谢都有可能的生理联系的候选基因。COMT rs4680是一种研究广泛且非常常见的基因多态，它会导致酶活性降低3-4倍。在女性(基因组)健康研究中，编码该酶低活性形式的COMT基因变异与心血管疾病风险增加以及甘油三酯、收缩压和血红蛋白A1c水平较高相关(N=23,294)。有趣的是，在这项研究的10年中，随机接受阿司匹林治疗的COMT低活性基因型纯合子女性的心血管疾病发生率较低。相反，与安慰剂相比，随机服用阿司匹林的COMT高活性纯合子女性心血管疾病发生率更高。鉴于阿司匹林在预防心血管疾病中的广泛应用，以及COMT rs4680基因变异的高患病率，我们迫切需要了解COMT基因座本身以及可能与其共享共同分子途径和网络的药物的概括性、机制和影响。这项翻译研究建议通过以下方式解决这些空白：1)在多民族队列中进行COMT与亚临床和临床心血管疾病发病率的流行病学研究；2)使用大规模的基因表达和药物基因组数据来阐明COMT的分子途径和相互作用的药物；以及3)进行临床研究，以检验这些药物对体外和体内血小板功能的影响。作为一种具有多效性心血管疾病和药物相互作用效应的新兴遗传基因座，COMT是探索涉及心血管功能、疾病和治疗的多个分子通路和网络的优秀模式系统，从而指导降低心血管疾病风险的新策略的开发，以及在心血管流行病学、系统生物学、临床试验和其他关键职业发展里程碑方面发展个人专长的一个有前途的范例。(摘要结束)