Population-based pharmacogenomic assessment of QT prolongation

摘要 常用处方药的心脏毒性，通常通过下列心电图特征来评估 作为QT间期的延长，是一个相关的临床主题，因为它具有调节后果(标记 和停药)，并与可能致命的患者水平的结果(室性心律失常)有关 和Torsade de Pointes)。我们建议在这里利用广泛的表型和遗传型数据资源 北加州凯撒永久(KPNC)基因、环境和健康研究计划 (RPGEH)，以及将这些数据链接到其他健康计划数据库的能力，即我们的药房， 心电图和门诊/住院病人利用数据库。特别是，我们将使用基因 成人健康和老龄流行病学研究(GERA)队列成员(n=110,266；n=69,276，其中1或 更多可用的ECG；具有两个或更多ECG的52,667个)。我们对QT进行纵向分析的能力 在一个庞大和种族多元化的人口中，间隔长达20年(Gera队列中78%是高加索人， 6%的亚洲/太平洋岛民，6%的拉丁裔，3%的非裔美国人，5%的其他人或混血儿)，并识别和 表征影响药物不良反应的遗传基因是独一无二的，并将促进我们对 常见处方药心脏毒性的遗传基础。在欧洲人身上重复研究结果 将在英国生物库中有心电图、全基因组和药物数据的70,944名高加索受试者中寻找。 我们将对复制的命中进行功能注释，以阐明生物途径和组织 牵涉其中。此外，为了补充这一方法，并更全面地解决下游临床 QT间期延长的意义，我们还将检查：a)发生室性心律失常的遗传预测因素 和Torsade de Pointes；b)通过药物相互作用确定的基因是否与这些 不良结局和c)QT间期延长的调解程度。我们的结果将与 用于复制和荟萃分析的药物基因组学研究网络(PGRN)。我们的长期合作 目标是推进药物心脏毒性的遗传基础及其下游领域的研究 将为治疗考虑提供参考的后果。

Abstract Cardiotoxicity of commonly prescribed medications, typically assessed by electrocardiographic features such as prolongation of the QT interval, is a relevant clinical topic because it has regulatory consequences (labelling and withdrawal of drugs) and is associated with potentially fatal patient-level outcomes (ventricular arrhythmias and Torsade de Pointes). We propose here to leverage the extensive phenotypic and genotypic data resources of the Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment and Health (RPGEH), and the ability to link these data to other health plan databases, namely our pharmacy, electrocardiogram (ECG) and outpatient/inpatient utilization databases. In particular, we will use the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort members (n=110,266; n=69,276 with 1 or more available ECGs; 52,667 with two or more ECGs). Our ability to conduct longitudinal analyses of the QT interval over up to 20 years in a large and ethnically diverse population (The GERA cohort is 78% Caucasian, 6% Asian/Pacific Islander, 6% Latino, 3% African-American, 5% other or mixed) and to identify and characterize genetic loci that influence adverse drug reactions is unique and will advance our understanding of the genetic basis of cardiac toxicity of commonly prescribed medications. Replication of findings in Europeans will be sought in 70,944 Caucasian subjects with ECG, genome-wide and medication data in the UK Biobank. We will perform functional annotation of replicated hits to shed light on biological pathways and tissues involved. In addition, to complement this approach and to more fully address the downstream clinical significance of QT prolongation, we will also examine: a) genetic predictors of incident ventricular arrhythmias and of Torsade de Pointes; b) whether the identified gene by drug interactions are associated with these adverse outcomes and c) degree of mediation by QTc prolongation. Our results will be shared with the Pharmacogenomics Research Network (PGRN) for replication and meta-analytical purposes. Our long-term goal is to advance the field of the genetic basis of drug cardiotoxicity and its downstream consequences that will inform therapeutic considerations.