Pharmacogenetics and Personalized Medicine after Cardiac Surgery in Children

儿童心脏手术后的药物遗传学和个体化医疗

• 批准号: 9324339
• 负责人: Todd L Edwards
• 金额: $ 64.53万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324339
• 关键词: 1 year old; Adult; Adverse effects; Affect; Agonist; Antibiotics; Area; Arrhythmia; Atrial Tachycardia; Birth; Blood specimen; Bradyarrhythmias; Candidate Disease Gene; Cardiac Surgery procedures; Cardiopulmonary Bypass; Caring; Cessation of life; Child; Childhood; Clinical; Cohort Studies; Collection; Complication; Computerized Medical Record; Congenital Abnormality; Consent; Coupled; DNA; Data; Databases; Dexmedetomidine; Dose; Drug Kinetics; Enrollment; Genes; Genetic Predisposition to Disease; Genetic Risk; Genotype; Goals; Healthcare; Heart Atrium; Human; Infant; Infant Mortality; Lead; Link; Mass Spectrum Analysis; Medicine; Meta-Analysis; Methods; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Patient risk; Patient-Focused Outcomes; Patients; Perioperative; Perioperative Care; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Pharmacology; Pharmacotherapy; Phenotype; Plasma; Positioning Attribute; Postoperative Care; Postoperative Complications; Postoperative Period; Public Health; Publishing; Research; Resources; Risk; Risk Factors; Sampling; Specific qualifier value; Tachyarrhythmias; Techniques; Testing; United States; Variant; Vasoconstrictor Agents; adverse outcome; base; clinical risk; cohort; congenital heart disorder; cost efficient; design; environmental stressor; gene interaction; genetic variant; genome-wide; improved; individual patient; individualized medicine; interpatient variability; mortality; multiple drug use; operation; palliation; personalized approach; personalized medicine; programs; prospective; receptor; repaired; response; sedative; treatment planning

Project Summary Congenital heart disease (CHD) is the most common human congenital malformation, and represents a leading cause of infant mortality. Roughly half of children with CHD will require surgical repairs/palliations, and are at risk for postoperative complications. Arrhythmias are common after CHD surgery, contribute substantially to morbidity and mortality, and are important long-term concerns for the more than 1 million US adults living with CHD. An individual patient's risk for arrhythmias is variable and not predicted by clinical factors alone, thus we hypothesize that genetic variants predispose patients to these serious complications. Dexmedetomidine is a widely used sedative after CHD surgery but is associated with marked inter-patient variability in efficacy, and potential adverse effects including bradyarrhythmias. Previous studies in adults have demonstrated genetic variants that alter dexmedetomidine pharmacodynamics, but studies in children have not been performed. The long term goal of this research program is to identify genetic variants that affect adverse outcomes after CHD surgery, along with actionable pharmacogenetic (drug-gene) interactions, in order to perform pre-operative genotyping and incorporation of genetic and clinical risk factors into individualized treatment plans, ultimately improving the care and reducing mortality and morbidity for patients with CHD. In order to achieve these goals, we established an ongoing cohort of over 1,600 children undergoing more than 2,200 CHD surgical procedures with detailed phenotypic information, coupled with DNA samples. Further, we have developed methods using mass spectrometry to accurately determine drug concentrations using small sample volumes (100µL plasma) enabling the use of leftover plasma from blood samples obtained for clinical purposes to probe disposition of drugs such as dexmedetomidine. In Specific Aim 1, we will test the hypothesis that genetic variants are associated with atrial arrhythmias after CHD surgery in children under 1 year of age. In Specific Aim 2 we will test the hypothesis that genetic variants alter pharmacokinetics and pharmacodynamics of dexmedetomidine after CHD surgery in children. Accomplishing these aims will ultimately lead to a personalized approach to care and improve clinical outcomes for patients with CHD.

项目概要 先天性心脏病（CHD）是最常见的人类先天性畸形，代表了一种 大约一半的先心病儿童需要手术修复/姑息治疗，以及 心律失常在 CHD 手术后很常见，有助于预防术后并发症。 严重影响发病率和死亡率，并且是超过 100 万美国人长期关注的重要问题 患有先心病的成人患者发生心律失常的风险是可变的，并且无法通过临床预测。 因此，仅就因素而言，我们面临的是遗传变异使患者容易出现这些严重并发症的情况。 右美托咪定是一种在 CHD 手术后广泛使用的镇静剂，但与明显的患者间反应有关 先前针对成人的研究表明，疗效存在差异，并且存在潜在的不良反应（包括缓慢性心律失常）。 改变右美托咪定的基因变异已证明其药效学，但儿童研究尚未证实 该研究计划的长期目标是确定影响不利的遗传变异。 CHD 手术后的结果，以及可操作的药物遗传学（药物基因）相互作用，以便 进行术前基因分型，并将遗传和临床危险因素纳入个体化治疗中 治疗计划，最终改善冠心病患者的护理并降低死亡率和发病率。 为了实现这些目标，我们建立了一个由 1,600 多名儿童组成的持续队列，接受超过 2,200 例 CHD 外科手术以及详细的表型信息以及 DNA 样本。 已经开发出使用质谱法的方法，可以使用小分子精确测定药物浓度 样本量（100 µL 血浆），可以使用临床血液样本中剩余的血浆 目的是探讨右美托咪定等药物的处置情况。在具体目标 1 中，我们将检验假设。 遗传变异与 1 岁以下儿童先心病手术后房性心律失常有关。 在具体目标 2 中，我们将检验遗传变异改变药代动力学的假设， 儿童先心病手术后右美托咪定的药效学将实现这些目标。 最终为冠心病患者提供个性化的护理方法并改善临床结果。