Prospective meta-analyses of drug-gene interactions: CHARGE GWAS consortium

药物-基因相互作用的前瞻性荟萃分析：CHARGE GWAS 联盟

• 批准号: 8105534
• 负责人: Bruce M Psaty
• 金额: $ 139.82万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-10 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105534
• 关键词: Abbreviations; Address; Adrenergic beta-Antagonists; Adverse drug effect; Adverse reactions; Affect; African American; Aging; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antidepressive Agents; Antidiabetic Drugs; Antihistamines; Aspirin; Atherosclerosis; Atrial Fibrillation; Body Composition; Calcium Channel Blockers; Candidate Disease Gene; Cardiovascular system; Clinical; Cohort Studies; Communities; Complement; Complex; Consensus; Coronary artery; Data; Development; Digitalis preparation; Disease; Diuretics; Drops; Drug Prescriptions; Drug usage; Electrocardiogram; Environment; Environmental Exposure; Epidemiology; Estrogens; Event; Failure; Framingham Heart Study; Genes; Genetic; Genetic Variation; Genomics; Genotype; Health; Health Benefit; Heart; Heart Rate; Hemorrhage; Heritability; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lead; Measures; Meta-Analysis; Methods; Modeling; Myocardial; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Participant; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Phenotype; Postmenopause; Potassium; Predisposition; Prevalence; Renal function; Research; Research Personnel; Resources; Risk; Safety; Serum; Suggestion; Sulfonylurea Compounds; Therapeutic Effect; Thiazide Diuretics; Variant; Warfarin; aging gene; base; clinical application; cohort; data sharing; experience; gene environment interaction; gene interaction; genetic variant; genome wide association study; genome-wide; interest; member; novel; population based; prospective; public health relevance; response; trait; working group; young adult

DESCRIPTION (provided by applicant): The benefits of modern drug therapies can be maximized by avoiding some medications in patients who are genetically susceptible to adverse reactions or by selecting other medications for patients who are genetically likely to benefit. Pharmacogenetic studies have usually relied on candidate-gene approaches; yet clinical applications with demonstrated health benefits remain few or far off. Recently, genome-wide association studies (GWAS) have discovered a large number of common genetic loci associated with complex disorders. GWAS methods to identify novel variants and pathways that affect drug response can complement the candidate-gene approaches. The setting is the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, formed to facilitate GWAS meta-analyses among multiple large population-based prospective cohort studies, including Age, Gene/ Environment Susceptibility Study, Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study, and the Rotterdam Study. Health ABC Study, the Multi-Ethnic Study of Atherosclerosis, the Coronary Artery Risk Development in Young Adults, and the Jackson Heart Study have joined the effort. The CHARGE data- sharing model has accelerated the discovery of novel genetic loci for complex diseases. With genome-wide data on more than 57,000 participants (22.4% African Americans), the proposed project will use GWAS methods to identify genetic loci that modify the effects of selected drugs on a variety of outcomes with a focus on unintended adverse drug effects. In this revised application, the primary aim involves the outcome of myocardial repolarization as assessed by the ECG QTc interval; and the four primary exposures of interest are: (1) use of high-torsades-risk QT-prolonging drugs (selected antiarrhythmics, antihistamines, antibiotics, and antidepressants); (2) sulfonylurea anti-diabetic agents; (3) thiazide diuretics, and (4) tri-cyclic and tetra- cyclic anti-depressants. In addition to this primary effort related to QTc, we plan to evaluate other potential drug-gene interactions such as the use of diuretics with serum potassium levels, the use of anti-depressants and diuretics with the ECG QRS interval, the use of beta-blockers and calcium antagonists and the PR interval, the use of aspirin with cardiovascular events ("aspirin failure" among aspirin users), and use of non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics with renal function. Public-health relevance: This broad-based discovery effort is likely to illuminate novel biologic mechanisms, affect how some drugs are prescribed, and identify novel targets for new therapies. PUBLIC HEALTH RELEVANCE: By leveraging the dense genotyping, deep phenotyping and diverse expertise, the PWG will accelerate the discovery of drug-gene interactions that may affect a variety of unintended therapeutic effects. The proposed project is likely to identify new variants and new pathways that affect drug response and drug safety.

描述（由申请人提供）：通过避免在遗传上容易受到不良反应的患者中的某些药物或为遗传上可能受益的患者选择其他药物，可以最大程度地提高现代药物疗法的好处。药物遗传学研究通常依赖于候选基因方法。然而，具有证明健康益处的临床应用仍然很少或遥不可及。最近，全基因组关联研究（GWAS）发现了大量与复杂疾病相关的常见遗传基因座。鉴定影响药物反应的新型变异和途径的GWAS方法可以补充候选基因方法。该环境是基因组流行病学（CHALL）联盟的心脏和衰老研究的人群，该联盟旨在促进多个基于人群的大型前瞻性研究研究中的GWAS荟萃分析，包括年龄，基因/环境易感研究，动脉粥样硬化研究，动脉粥样硬化的风险，社区中的动脉粥样硬化风险，心血管健康研究，心血管健康，心脏病心脏研究，framingham Heartham Hearts研究和哥特式研究。卫生ABC研究，动脉粥样硬化的多民族研究，年轻人的冠状动脉风险发展以及杰克逊心脏的研究加入了这项工作。电荷数据共享模型已加速了针对复杂疾病的新遗传基因座的发现。借助有关57,000多名参与者（22.4％非裔美国人）的全基因组数据，该项目将使用GWAS方法来识别遗传基因座，以改变所选药物对各种结果的影响，重点是意外的不良药物影响。在此修订后的应用中，主要目的涉及通过ECG QTC间隔评估的心肌复极的结果。感兴趣的四个主要暴露是：（1）使用高压风险的QT繁殖药物（选定的抗心律失常，抗组胺药，抗生素和抗抑郁药）； （2）磺酰脲抗糖尿病药物； （3）噻嗪类利尿剂，以及（4）三环和四环抗抑制剂。除了与QTC相关的这一主要努力外，我们计划评估其他潜在的药物 - 基因相互作用，例如使用具有血清钾水平的利尿剂，使用抗抑郁药和ECG QRS间隔的使用和利尿剂，在使用β-阻滞剂和beta阻滞剂和钙拮抗剂和PR Interval的使用中，使用了Absifin and Cardiovinal and Cardiovaline（Avelival）（Absioval Cardioval）（'Avelioval）（Avelival）（'Avelival）（'Absiovascult）（'Aveliovalcascult）（“''Absiovascult revercasscascult nevel（“”'''''''非甾体类抗炎药，血管紧张素转化酶抑制剂，血管紧张素受体阻滞剂和具有肾功能的利尿剂。公共卫生相关性：这种基于广泛的发现工作可能会阐明新颖的生物学机制，影响某些药物的处方方式，并确定新疗法的新靶标。 公共卫生相关性：通过利用密集的基因分型，深厚的表型和多样化的专业知识，PWG将加速可能影响各种意外治疗作用的药物 - 基因相互作用。拟议的项目可能会确定影响药物反应和药物安全的新变体和新途径。