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

 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，特别强调儿茶酚-O-甲基转移酶（COMT）在心血管疾病（CVD）和预防性治疗中的作用。尽管在预防和管理方面取得了重大进展，但CVD仍然是美国的主要死亡原因。药物基因组学，研究个体的基因组如何影响他们的治疗反应，扩大了我们对CVD的病理生理学和治疗的理解。然而，基因-药物相互作用在流行病学和临床研究中很难评估，部分原因是这些相互作用的全基因组关联研究所需的样本量非常大，并且缺乏强有力的候选基因。COMT是一个强有力的候选基因，它编码降解包括肾上腺素、去甲肾上腺素和儿茶酚雌激素在内的儿茶酚胺的关键酶，与CVD和药物代谢都有可能存在生理联系。COMT rs 4680是一种经过充分研究且极其常见的遗传多态性，其导致酶活性降低3-4倍。在女性（基因组）健康研究（N= 23，294）中，编码低活性形式酶的COMT遗传变异与CVD风险增加和甘油三酯、收缩压和血红蛋白A1 c水平升高相关。有趣的是，在10年的研究中，随机接受阿司匹林治疗的COMT低活性基因型纯合子女性CVD的发病率较低。相反，COMT高活性纯合子女性随机接受阿司匹林治疗的CVD发生率高于安慰剂组。鉴于阿司匹林广泛用于预防心血管疾病，以及COMT rs 4680遗传变异的高患病率，我们必须了解COMT基因座本身的普遍性，机制和影响，以及可能与其共享共同分子途径和网络的药物。这项转化研究提案通过以下方式解决这些差距：1）在多种族队列中COMT与亚临床和临床CVD发病率相关的流行病学研究; 2）使用大规模基因表达和药物基因组学数据来阐明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离体和体内血小板功能的影响。作为一个新兴的具有多效性CVD和药物相互作用效应的遗传位点，COMT是一个很好的模型系统，可以探索涉及心血管功能，疾病和治疗的多分子通路和网络，从而指导开发新的策略来降低CVD风险，并且是一个有希望的例子，可以在心血管流行病学，系统生物学，临床试验，以及其他重要的职业发展里程碑。(End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)