Pharmacogenetics and Personalized Medicine after Cardiac Surgery in Children

项目摘要 先天性心脏病(CHD)是人类最常见的先天性畸形，是一种 婴儿死亡的主要原因。大约一半患有先天性心脏病的儿童需要手术修复/姑息， 有发生术后并发症的风险。心律失常是冠心病手术后常见的原因之一 极大地增加了发病率和死亡率，是100多万美国人长期关注的重要问题 成年冠心病患者。单个患者发生心律失常的风险是可变的，临床上无法预测 单独的因素，因此我们假设基因变异使患者容易发生这些严重的并发症。 右美托咪定是冠心病手术后广泛使用的镇静剂，但与明显的住院患者有关 疗效的可变性，以及包括缓慢性心律失常在内的潜在不良反应。之前对成年人的研究已经 证实了改变右美托咪定药效的遗传变异，但在儿童中的研究还没有 已经完成了。这项研究计划的长期目标是识别影响不良反应的基因变异 冠心病手术后的结果，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，并将遗传和临床风险因素纳入个体化 治疗计划，最终改善护理，降低冠心病患者的死亡率和发病率。在……里面 为了实现这些目标，我们建立了一个由1600多名儿童组成的持续队列，他们正在接受超过 2,200例冠心病手术，包括详细的表型信息，以及DNA样本。此外，我们 已经开发出使用质谱学的方法来准确地确定药物浓度 采样量(100ug L血浆)允许使用临床采集的血液样本中的剩余血浆 目的探讨右旋美托咪定等药物的处置。在具体目标1中，我们将检验假设 基因变异与1岁以下儿童先心病手术后房性心律失常有关。 在特定目标2中，我们将检验以下假设：基因变异改变药代动力学和 右美托咪定在儿童冠心病术后的药效学研究。实现这些目标将 最终导致一种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.