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
基本信息
- 批准号:8668128
- 负责人:
- 金额:$ 134.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-08-10 至 2017-05-31
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAddressAdrenergic beta-AntagonistsAdverse drug effectAdverse reactionsAffectAfrican AmericanAgingAngiotensin ReceptorAngiotensin-Converting Enzyme InhibitorsAnti-Inflammatory AgentsAnti-inflammatoryAntibioticsAntidepressive AgentsAntidiabetic DrugsAntihistaminesAspirinAtherosclerosisAtrial FibrillationBody CompositionCalcium Channel BlockersCandidate Disease GeneCardiovascular systemClinicalCohort StudiesCommunitiesComplementComplexConsensusCoronary arteryDataDevelopmentDigitalis preparationDiseaseDiureticsDropsDrug PrescriptionsDrug usageElectrocardiogramEnvironmentEnvironmental ExposureEpidemiologyEstrogensEventFailureFramingham Heart StudyGenesGeneticGenomicsGenotypeHealthHealth BenefitHeartHeart RateHemorrhageHeritabilityHydroxymethylglutaryl-CoA Reductase InhibitorsJackson Heart StudyLeadMeasuresMeta-AnalysisMethodsModelingMyocardialNon-Insulin-Dependent Diabetes MellitusOutcomeParticipantPathway interactionsPatientsPharmaceutical PreparationsPharmacogeneticsPharmacotherapyPhenotypePostmenopausePotassiumPredispositionPrevalenceRenal functionResearchResearch PersonnelResourcesRiskSafetySerumSuggestionSulfonylurea CompoundsTherapeutic EffectThiazide DiureticsVariantWarfarinaging genebaseclinical applicationcohortdata sharingexperiencegene environment interactiongene interactiongenetic variantgenome wide association studygenome-wideinterestmembernovelpopulation basedprospectivepublic health relevancerare variantresponsetraitworking groupyoung adult
项目摘要
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.
描述(由申请人提供):通过避免对遗传上易受不良反应影响的患者使用某些药物,或为遗传上可能受益的患者选择其他药物,可以最大限度地发挥现代药物疗法的益处。药物遗传学研究通常依赖于候选基因方法。然而,已证明对健康有益的临床应用仍然很少或还很遥远。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。识别影响药物反应的新变异和途径的 GWAS 方法可以补充候选基因方法。该机构是基因组流行病学心脏与衰老研究队列 (CHARGE) 联盟,该联盟的成立是为了促进多个基于人群的前瞻性队列研究的 GWAS 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、心血管疾病健康研究、弗雷明汉心脏研究和鹿特丹研究。 Health ABC 研究、动脉粥样硬化多种族研究、年轻人冠状动脉风险发展以及杰克逊心脏研究也加入了这一努力。 CHARGE 数据共享模型加速了复杂疾病新遗传位点的发现。凭借超过 57,000 名参与者(22.4% 非裔美国人)的全基因组数据,拟议项目将使用 GWAS 方法来识别基因位点,这些基因位点可以改变所选药物对各种结果的影响,重点关注意外的药物不良反应。在此修订后的应用程序中,主要目标涉及通过心电图 QTc 间期评估的心肌复极结果;感兴趣的四种主要暴露是: (1) 使用高扭转性室速风险的 QT 延长药物(选定的抗心律失常药、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。除了与 QTc 相关的主要工作外,我们还计划评估其他潜在的药物-基因相互作用,例如利尿剂与血清钾水平的使用、抗抑郁药和利尿剂与心电图 QRS 间期的使用、β-阻滞剂和钙拮抗剂以及 PR 间期、使用阿司匹林导致心血管事件(阿司匹林使用者中的“阿司匹林衰竭”)以及使用非甾体类抗炎药、血管紧张素转换酶抑制剂、血管紧张素受体阻滞剂和具有肾功能的利尿剂。公共卫生相关性:这项基础广泛的发现工作可能会阐明新的生物学机制,影响某些药物的处方方式,并确定新疗法的新靶标。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bruce M Psaty其他文献
Bruce M Psaty的其他文献
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{{ truncateString('Bruce M Psaty', 18)}}的其他基金
Innate and adaptive immune-cell densities as risk factors for heart failure
先天性和适应性免疫细胞密度是心力衰竭的危险因素
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10226411 - 财政年份:2018
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Rare variants and NHLBI traits in deeply phenotyped cohorts
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9334955 - 财政年份:2014
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Rare variants and NHLBI traits in deeply phenotyped cohorts
深度表型队列中的罕见变异和 NHLBI 特征
- 批准号:
8930265 - 财政年份:2014
- 资助金额:
$ 134.45万 - 项目类别:
Rare variants and NHLBI traits in deeply phenotyped cohorts
深度表型队列中的罕见变异和 NHLBI 特征
- 批准号:
8683958 - 财政年份:2014
- 资助金额:
$ 134.45万 - 项目类别:
T-cell subsets as CVD risk factors in CHS and MESA
T 细胞亚群作为 CHS 和 MESA 的 CVD 危险因素
- 批准号:
8890872 - 财政年份:2014
- 资助金额:
$ 134.45万 - 项目类别:
Rare variants and NHLBI traits in deeply phenotyped cohorts
深度表型队列中的罕见变异和 NHLBI 特征
- 批准号:
9034657 - 财政年份:2014
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T-cell subsets as CVD risk factors in CHS and MESA
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9055750 - 财政年份:2014
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$ 134.45万 - 项目类别:
T-cell subsets as CVD risk factors in CHS and MESA
T 细胞亚群作为 CHS 和 MESA 的 CVD 危险因素
- 批准号:
8755241 - 财政年份:2014
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$ 134.45万 - 项目类别:
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
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$ 134.45万 - 项目类别:
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
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8470694 - 财政年份:2011
- 资助金额:
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