Pharmacogenetics and Personalized Medicine after Cardiac Surgery in Children

项目摘要 先天性心脏病（CHD）是最常见的人类先天性畸形，并且代表了一种先天性心脏病。 婴儿死亡的主要原因。大约一半的CHD儿童需要手术修复/姑息治疗， 有术后并发症的风险冠心病手术后心律失常很常见， 严重影响发病率和死亡率，并且是超过100万美国人的重要长期问题。 成人CHD患者。个体患者的心律失常风险是可变的，临床无法预测。 因此，我们假设遗传变异使患者易患这些严重并发症。 右美托咪定是冠心病手术后广泛使用的镇静剂，但与显著的患者间 疗效的变异性和潜在的不良反应，包括缓慢性心律失常。以前在成人中的研究 证明了改变右美托咪定药效学的遗传变异，但在儿童中的研究没有 被执行。这项研究计划的长期目标是确定影响不良反应的遗传变异。 CHD手术后的结局，沿着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，并将遗传和临床风险因素纳入个体化 治疗计划，最终改善冠心病患者的护理，降低死亡率和发病率。在 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， 2，200例CHD外科手术，包含详细的表型信息，以及DNA样本。我们还 已经开发了使用质谱法的方法，以使用小的 样本量（100µL血浆），能够使用临床采集的血液样本中的剩余血浆 目的是探测药物如右美托咪定的处置。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CHD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， 右美托咪定在儿童冠心病手术后的药效学。实现这些目标将 最终导致个性化的方法来护理和改善冠心病患者的临床结果。

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.