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: 10438085
• 负责人: Kathryn Tayo Hall
• 金额: $ 5.16万
• 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 2021-10-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438085
• 关键词: Acute; Address; Adherence; Affect; Age; Agonist; Alleles; Amino Acids; Antiplatelet Drugs; Aspirin; Atherosclerosis; Attenuated; Biological Models; Blood Platelets; COVID-19 pandemic; Candidate Disease Gene; Capital; Cardiac Surgery procedures; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Catechol Estrogens; Catechol O-Methyltransferase; Catecholamines; Cause of Death; Clinical; Clinical Research; Clinical Trials; Complex; Coronary; Data; Death Rate; Development; Disease; Dopamine; Dose; Drug Interactions; Drug usage; Endocrine; Ensure; Enzymes; Epidemiology; Epinephrine; Estrogen Replacement Therapy; Estrogen Replacements; Event; Fibrinogen; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genome; Genotype; Goals; Gold; Grant; Hemorrhage; Hemostatic function; Heritability; Heterozygote; Homozygote; Hyperhomocysteinemia; Individual; Investments; Lead; Link; Lipids; Membrane; Mentored Research Scientist Development Award; Methionine; Molecular; Myocardial Infarction; Norepinephrine; Participant; Pathway interactions; Pharmaceutical Preparations; Pharmacogenomics; Physiological; Placebos; Platelet Activation; Platelet aggregation; Play; Pre-Eclampsia; Predisposition; Prevention; Prevention trial; Preventive treatment; Public Health; Publications; Quercetin; Randomized; Randomized Clinical Trials; Research; Research Personnel; Research Proposals; Resources; Rest; Risk; Role; Sample Size; Signaling Molecule; Single Nucleotide Polymorphism; Stress; Stroke; Surface; Systems Biology; Testing; Training; Translational Research; United States; Valine; Variant; Vitamin B 12; Woman; Women' s Health; Work; attributable mortality; base; cardiovascular disorder epidemiology; cardiovascular disorder prevention; cardiovascular disorder risk; career development; drug efficacy; drug metabolism; epidemiology study; experience; gene interaction; genetic variant; genome wide association study; genome-wide analysis; genomic data; genomic locus; healthy volunteer; high dimensionality; individual response; individualized prevention; innovation; insight; medication safety; methionylmethionine; multi-ethnic; novel; novel strategies; personalized medicine; platelet function; response; screening; treatment response

PROJECT SUMMARY / ABSTRACT Extension of the funding for this K01 award will support completion of a critical career development goal 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. The extension is warranted because of delays resultING from the COVID-19 pandemic. 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 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. Through this K01 we demonstrated COMT genetic effects on CVD risk with aspirin and estrogen replacement in the Multiethnic Study of Atherosclerosis, supporting our earlier findings in the Women’s Health Study. Given the widespread use of aspirin for prevention of CVD, 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 conducting a clinical trial to examine effects of native aspirin on platelet function as a function of COMT genotype. 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.

项目摘要/摘要 延长这一K01奖项的资金将支持完成一个关键的职业发展目标 心血管流行病学和药物基因组学初级研究员，特别强调 儿茶酚-O-甲基转移酶(COMT)与心血管疾病的关系及预防治疗这个 延期是有理由的，因为新冠肺炎疫情造成了延误。尽管取得了长足的进步 在预防和管理方面，心血管疾病仍然是美国的主要死亡原因。 药物基因组学，即研究个体的基因组如何影响他们的治疗反应的研究已经扩大 我们对CVD的病理生理学和治疗的理解。然而，基因-药物相互作用一直是 在流行病学和临床研究中难以评估，部分原因是需要大量样本 对这些相互作用和缺乏强有力的候选基因的全基因组关联研究。Comt，其中 编码降解儿茶酚胺的关键酶，包括肾上腺素、去甲肾上腺素和儿茶酚 雌激素，是一个可能与心血管疾病和药物代谢相关的候选基因。 通过这个K01，我们展示了COMT基因对阿司匹林和雌激素替代治疗心血管疾病风险的影响。 在动脉粥样硬化的多种族研究中，支持了我们在女性健康研究中的早期发现。vt.给出 由于阿司匹林在预防心血管疾病中的广泛使用，我们必须了解其普遍性， COMT基因座本身和可能共享共同分子途径和基因的药物的机制和影响 与之相关的网络。这项转化性研究提案通过进行临床试验来解决这些差距 检测国产阿司匹林对COMT基因对血小板功能的影响。作为一种新兴的基因 具有多效性CVD和药物相互作用效应的基因座，COMT是一个很好的模型系统 参与心血管功能、疾病和治疗的多个分子通路和网络，从而 指导开发降低心血管疾病风险的新战略，并成为发展的有前途的范例 在心血管流行病学、系统生物学、临床试验和其他关键职业方面的个人专长 发展里程碑。

项目成果

Catechol-O-Methyltransferase moderates effect of stress mindset on affect and cognition.

• DOI: 10.1371/journal.pone.0195883
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Crum AJ;Akinola M;Turnwald BP;Kaptchuk TJ;Hall KT
• 通讯作者: Hall KT

Network analysis of the genomic basis of the placebo effect.

安慰剂效应的基因组基础的网络分析。

• DOI: 10.1172/jci.insight.93911
• 发表时间: 2017
• 期刊: JCI insight
• 影响因子: 8
• 作者: Wang,Rui-Sheng;Hall,KathrynT;Giulianini,Franco;Passow,Dani;Kaptchuk,TedJ;Loscalzo,Joseph
• 通讯作者: Loscalzo,Joseph

Genomic Effects Associated With Response to Placebo Treatment in a Randomized Trial of Irritable Bowel Syndrome.

• DOI: 10.3389/fpain.2021.775386
• 发表时间: 2021
• 期刊: Frontiers in pain research (Lausanne, Switzerland)
• 作者: Wang RS;Lembo AJ;Kaptchuk TJ;Cheng V;Nee J;Iturrino J;Rao M;Loscalzo J;Silvester JA;Hall KT
• 通讯作者: Hall KT

Open-label versus double-blind placebo treatment in irritable bowel syndrome: study protocol for a randomized controlled trial.

• DOI: 10.1186/s13063-017-1964-x
• 发表时间: 2017-05-25
• 期刊: Trials
• 影响因子: 2.5
• 作者: Ballou S;Kaptchuk TJ;Hirsch W;Nee J;Iturrino J;Hall KT;Kelley JM;Cheng V;Kirsch I;Jacobson E;Conboy L;Lembo A;Davis RB
• 通讯作者: Davis RB

Genotypes of Pain and Analgesia in a Randomized Trial of Irritable Bowel Syndrome.

• DOI: 10.3389/fpsyt.2022.842030
• 发表时间: 2022
• 期刊: Frontiers in psychiatry
• 影响因子: 4.7
• 作者: Vollert J;Wang R;Regis S;Yetman H;Lembo AJ;Kaptchuk TJ;Cheng V;Nee J;Iturrino J;Loscalzo J;Hall KT;Silvester JA
• 通讯作者: Silvester JA