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

描述（由申请人提供）：通过避免遗传上易受不良反应影响的患者使用某些药物或选择遗传上可能获益的患者使用其他药物，可以最大限度地发挥现代药物治疗的获益。药物遗传学研究通常依赖于候选基因的方法，但临床应用证明健康的好处仍然很少或遥远。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位点。GWAS方法鉴定影响药物反应的新变体和途径可以补充候选基因方法。该研究的背景是基因组流行病学中心脏和衰老研究队列（CHARGE）联盟，该联盟旨在促进GWAS在多个大型基于人群的前瞻性队列研究中的荟萃分析，包括年龄、基因/环境易感性研究、社区动脉粥样硬化风险、心血管健康研究、心脏病研究和鹿特丹研究。健康ABC研究，动脉粥样硬化的多种族研究，年轻人冠状动脉风险发展和杰克逊心脏研究已经加入了这一努力。CHARGE数据共享模式加速了复杂疾病的新基因位点的发现。根据超过57，000名参与者（22.4%为非洲裔美国人）的全基因组数据，拟议的项目将使用GWAS方法来确定遗传位点，这些基因位点可以改变选定药物对各种结果的影响，重点是非预期的药物不良反应。在本修订申请中，主要目的涉及通过ECG QTc间期评估的心肌复极结局;关注的四种主要暴露为：（1）使用高风险的扭转型室性心动过速延长药物（选定的抗抑郁药、抗组胺药、抗生素和抗抑郁药）;（2）磺酰脲类抗糖尿病药;（3）噻嗪类利尿剂，和（4）三环和四环抗抑郁药。除了这项与QTc相关的主要工作外，我们计划评估其他潜在的药物-基因相互作用，例如使用利尿剂与血清钾水平、使用抗抑郁药和利尿剂与ECG QRS间期、使用β受体阻滞剂和钙拮抗剂与PR间期、使用阿司匹林与心血管事件（阿司匹林使用者中的“阿司匹林失败”），以及使用非甾体抗炎药、血管紧张素转换酶抑制剂、血管紧张素受体阻滞剂和利尿剂与肾功能有关。公共卫生相关性：这种基础广泛的发现努力可能会阐明新的生物学机制，影响一些药物的处方方式，并确定新疗法的新靶点。 公共卫生相关性：通过利用密集的基因分型，深入的表型和多样化的专业知识，PWG将加速发现可能影响各种非预期治疗效果的药物-基因相互作用。拟议的项目可能会发现影响药物反应和药物安全性的新变体和新途径。

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.