Population-based pharmacogenomic assessment of QT prolongation

基于人群的 QT 延长药物基因组学评估

基本信息

批准号：
9925250
负责人：
Carlos Iribarren
金额：
$ 75.46万
依托单位：
KAISER FOUNDATION RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925250
关键词：
6-Mercaptopurine Address Adult African American Aging Alternative Therapies American Antibiotics Antidepressive Agents Antifungal Agents Asians Biological CYP2C19 gene California Candidate Disease Gene Carbamazepine Cardiac Cardiotoxicity Cardiovascular system Caucasians Clinic Collaborations Complement Cross-Sectional Studies Data Databases Drug Interactions Electrocardiogram Environment Equation Ethnic group European Exposure to Genes Genetic Genetic Predisposition to Disease Genetic study Genotype Goals HLA-B Antigens Health Heart Heterogeneity Individual Inpatients Investigation Ion Channel Label Latino Light Link Literature Measures Mediating Mediation Meta-Analysis Minority Groups Modeling Names Outcome Outpatients Pacific Island Americans Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacology Pharmacy facility Phenotype Physicians Population Population Heterogeneity Predisposition Quantitative Trait Loci Research Research Personnel Risk Sampling Structure Sudden Death TPMT gene Testing Therapeutic Time Study Tissues Torsades de Pointes Translating United Kingdom Variant Ventricular Arrhythmia Work abacavir adjudicate adverse drug reaction adverse event risk adverse outcome biobank bioinformatics tool clinically relevant clinically significant clopidogrel cohort data resource design drug metabolism drug withdrawal epidemiology study ethnic diversity genetic epidemiology genetic predictors genetic testing genetic variant genome wide association study genome-wide genomic locus health plan heart rhythm longitudinal analysis member novel population based prevent programs side effect

项目摘要

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.

抽象的常用处方药物的心脏毒性，通常通过心电图特征进行评估，例如作为 QT 间期的延长，是一个相关的临床主题，因为它具有监管后果（标签和停药），并与潜在致命的患者水平结果（室性心律失常和尖端扭转型室速）。我们在此建议利用广泛的表型和基因型数据资源北加州凯撒医疗机构 (KPNC) 基因、环境与健康研究项目（RPGEH），以及将这些数据链接到其他健康计划数据库（即我们的药房）的能力，心电图 (ECG) 和门诊/住院患者利用数据库。特别是，我们将使用遗传成人健康和老龄化流行病学研究 (GERA) 队列成员（n=110,266；n=69,276，其中 1 或更多可用的心电图； 52,667 有两个或更多心电图）。我们对 QT 进行纵向分析的能力在一个庞大且种族多样化的人群中，间隔长达 20 年（GERA 队列中 78% 是白种人， 6% 亚洲/太平洋岛民、6% 拉丁裔、3% 非裔美国人、5% 其他或混血）并识别和表征影响药物不良反应的遗传位点是独特的，将增进我们对药物不良反应的理解常用处方药心脏毒性的遗传基础。在欧洲人中复制研究结果将在英国生物银行的 70,944 名白人受试者中寻找心电图、全基因组和药物数据。我们将对重复命中进行功能注释，以阐明生物途径和组织涉及。此外，为了补充这种方法并更全面地解决下游临床问题为了了解 QT 延长的重要性，我们还将检查：a) 室性心律失常的遗传预测因素和尖端扭转型室速； b) 通过药物相互作用鉴定的基因是否与这些相关不良后果和 c) QTc 延长的调节程度。我们的结果将与用于复制和荟萃分析目的的药物基因组学研究网络 (PGRN)。我们的长期目标是推进药物心脏毒性及其下游遗传基础领域的发展后果将指导治疗考虑。