Atrial Fibrillation Susceptibility Due to Genetic Variation at Chromosome 4q25

4q25 染色体遗传变异导致心房颤动的易感性

• 批准号: 9389477
• 负责人: Moore Benjamin Shoemaker
• 金额: $ 17.28万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-10 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9389477
• 关键词: 4q25; Ablation; Address; Adult; Affect; Animal Model; Anti-Arrhythmia Agents; Area; Arrhythmia; Atrial Fibrillation; Atrial Flutter; Atrial Tachycardia; Award; Cardiac; Cardiovascular system; Cessation of life; Chromosomes; Clinical; Clinical Pharmacology; Clinical Research; Clinical Sciences; Clinical Trials; Clinical Trials Design; Collection; Data; Dementia; Development; Development Plans; Electrophysiology (science); Enrollment; Environment; Epidemic; Exhibits; Experimental Models; Faculty; Funding; Future; Genes; Genetic; Genetic Markers; Genetic Transcription; Genetic Variation; Genotype; Goals; Grant; Heart Atrium; Heart failure; Human Genetics; Impaired cognition; Impairment; Individual; Intercistronic Region; K-Series Research Career Programs; Knowledge; Lead; Leadership; Left atrial structure; Length; Master of Science; Measurement; Measures; Mediating; Medical Genetics; Mentors; Mentorship; Methods; Morbidity - disease rate; Myocardial; Odds Ratio; Pathogenesis; Patients; Performance; Pharmaceutical Preparations; Pharmacogenomics; Pharmacotherapy; Phenotype; Physicians; Positioning Attribute; Predisposition; Principal Investigator; Procedures; Pulmonary veins; Recurrence; Refractory; Registries; Research; Research Methodology; Research Personnel; Research Proposals; Right atrial structure; Risk; Risk Factors; Science of genetics; Scientist; Services; Signal Transduction; Single Nucleotide Polymorphism; Site; Source; Standardization; Stroke; Structure; Subgroup; Susceptibility Gene; Tachyarrhythmias; Tachycardia; Techniques; Testing; Time; Training; Transgenic Mice; Translational Research; United States National Institutes of Health; Universities; Up-Regulation; base; biobank; career; career development; clinical investigation; cost; design; genetic epidemiology; genetic variant; genome wide association study; genomic biomarker; homeodomain; imaging modality; mortality; non-invasive imaging; patient oriented research; personalized medicine; prevent; programs; prospective; public health relevance; response; risk variant; skills; source localization; success; trait; transcription factor; treatment response; voltage

 DESCRIPTION (provided by applicant): Candidate: Dr. Shoemaker is a cardiac electrophysiologist with an advanced degree in patient-oriented research (Master of Science in Clinical Investigation). He joined faculty as a physician-scientist in July 2014 with plans to pursue a career studying the pharmacogenomics of cardiac arrhythmias. Dr. Shoemaker's shortterm goal is to understand the electrophysiologic (EP) mechanisms by which common genetic variants lead to atrial fibrillation (AF) and modulate clinical response to AF therapies. During the five years of this career development award, he plans to strengthen his understanding of clinical pharmacology and drug science, genetics, methods for quantitative trait analysis, and clinical trial design. Dr. Shoemaker's long-term goal is to establish a researc program focused on the development of personalized and pharmacogenomics-based approaches to AF therapy. The goal of his career development plan and complementary research proposal is to develop the skills and generate preliminary data to successfully compete for independent funding through R01 grant mechanisms. Environment: As both the coordinating center of the NIH's Clinical and Translational Science Award (CTSA) program, and lead site for the Pharmacogenomics of Arrhythmia Therapy (PAT) node of the Pharmacogenomics Research Network (PGRN), Vanderbilt University is ideally suited to provide Dr. Shoemaker cross-training in clinical investigation and pharmacogenomics research methods. He has a well established mentorship team with combined expertise in the genetics of arrhythmias, pharmacogenomics, and clinical trial design and implementation. Dr. Dawood Darbar is a clinical electrophysiologist and established physician-scientist with national leadership recognition in the human genetics of AF, and Director of the Vanderbilt Arrhythmia Service. Dr. C. Michael Stein is a clinical trialist with expertise in cardiovascular pharmacogenomics and previously Assistant Dean for Clinical and Translational Research Scientist Development. Dr. Roden is Assistant Vice Chancellor for Personalized Medicine and serves as Principal Investigator for several large federally-funded projects focused on implementation of pharmacogenomics including the PAT node of the PGRN. All three mentors are committed to Dr. Shoemaker's career development and have a track record of successfully mentoring young investigators. Research: We propose two Specific Aims that seek to define the EP mechanism(s) by which common genetic variants at the chromosome 4q25 locus contribute to AF susceptibility and modulate response to AF therapies. Phenotyping will be performed using standardized collection of intracardiac EP measurements in patients with AF undergoing ablation. The Specific Aims focus on single nucleotide polymorphisms (SNPs) at chromosome 4q25 that were identified by GWAS to be strongly associated with AF. They are suspected to be transcriptional regulators of a nearby gene, PITX2 (paired-like homeodomain transcription factor 2), which in transgenic mice has been found to regulate development of the pulmonary vein (PV) myocardial sleeve - a critical structure in AF pathogenesis, and result in pro-arrhythmic changes in atrial electrophysiology through adverse electrical and structural remodeling. While we have demonstrated that AF risk alleles at 4q25 predict an impaired clinical response to treatment with AF ablation and modulate response to antiarrhythmic drugs (AADs), the underlying mechanism(s) for these observations remains unknown. In Specific Aim 1, we seek to further our understanding of the effect of 4q25 risk allele carriers on PV myocardial sleeve size and changes in atrial refractoriness. These findings will not only advance our understanding of how 4q25 risk allele carriers respond to isolation of the PV myocardial sleeves (ablation) but also to specific AAD therapies, which mediate their effect by slowing either atrial repolarization or conduction velocity. In Specific Aim 2 we focus specifically on AF ablation by testing the hypothesis that 4q25 risk allele carriers who undergo AF ablation are more likely to have recurrence of atrial tachyarrhythias due to non-PV mediated AF sources. This finding would inform trials testing personalized AF ablation strategies based on 4q25 genotype. These Aims are designed to provide preliminary data for Dr. Shoemaker to propose future clinical trials investigating both personalization of AF ablation therapy and a pharmacogenomics-based approach to AAD therapy for this common and morbid condition.

 描述（由申请人提供）： 候选人：Shoemaker 博士是一位心脏电生理学家，拥有以患者为导向的研究高级学位（临床研究理学硕士），他于 2014 年 7 月作为医师兼科学家加入教职，并计划攻读博士学位。 Shoemaker 博士的职业生涯是研究心律失常的药物基因组学，其短期目标是了解常见遗传变异导致心房颤动的电生理 (EP) 机制。 (AF) 并调节对 AF 治疗的临床反应。在获得职业发展奖的五年期间，他计划加强对临床药理学和药物科学、遗传学、数量性状分析方法以及 Shoemaker 博士的临床试验设计的理解。长期目标是建立一个研究计划，专注于开发基于药物基因组学的个性化房颤治疗方法。他的职业发展计划和补充研究提案的目标是培养技能并生成初步数据，以成功争取独立。资金通过R01 拨款机制。 环境：作为 NIH 临床和转化科学奖 (CTSA) 计划的协调中心，以及药物基因组学研究网络 (PGRN) 心律失常治疗药物基因组学 (PAT) 节点的牵头站点，范德比尔特大学非常适合为博士提供舒梅克在临床研究和药物基因组学研究方法方面进行了交叉培训，他拥有一支完善的导师团队，拥有遗传学方面的综合专业知识。 Dawood Darbar 博士是一位临床电生理学家，也是一位在 AF 人类遗传学领域享有国家领导地位的医师科学家，C. Michael Stein 博士是范德比尔特心律失常服务中心的主任。 Roden 博士是一位临床试验专家，具有心血管药物基因组学方面的专业知识，曾任负责临床和转化研究科学家发展的助理院长，现任个性化医学助理副校长。作为几个大型联邦资助项目的首席研究员，重点关注药物基因组学的实施，包括 PGRN 的 PAT 节点。所有三位导师都致力于 Shoemaker 博士的职业发展，并拥有成功指导年轻研究人员的记录。 研究：我们提出了两个具体目标，旨在定义 EP 机制，通过该机制，染色体 4q25 位点的常见遗传变异有助于 AF 易感性并调节对 AF 治疗的反应，将使用心内 EP 测量的标准化收集进行表型分析。接受消融的 AF 患者的具体目标集中在染色体 4q25 上的单核苷酸多态性 (SNP)，GWAS 发现这些多态性与 AF 密切相关。它们被怀疑是附近基因 PITX2（配对样同源域转录因子 2）的转录调节因子，在转基因小鼠中已发现该基因可调节肺静脉 (PV) 心肌袖（AF 的关键结构）的发育。虽然我们已经证明 4q25 的 AF 风险等位基因预测治疗的临床反应受损，但通过不利的电和结构重塑，导致心房电生理学发生促心律失常的变化。随着 AF 消融和抗心律失常药物 (AAD) 的调节反应，这些观察结果的潜在机制仍然未知。在具体目标 1 中，我们寻求进一步了解 4q25 风险等位基因携带者对 PV 心肌袖大小和的影响。这些发现不仅将增进我们对 4q25 风险等位基因携带者如何应对 PV 心肌袖的反应的理解。 （消融），也涉及特定的 AAD 疗法，这些疗法通过减慢心房复极或传导速度来介导其效果。在特定目标 2 中，我们通过测试接受 AF 消融的 4q25 风险等位基因携带者更有可能发生的假设来特别关注 AF 消融。由于非 PV 介导的 AF 来源而导致房性快速心律失常复发，这一发现将为测试基于 4q25 基因型的个性化 AF 消融策略的试验提供信息。这些目标旨在为 Shoemaker 博士提供初步数据，以提出未来的临床试验，研究 AF 消融治疗的个性化以及针对这种常见病态的 AAD 治疗的药物基因组学方法。