PHARMACOGENETICS AND RESPONSE TO THERAPY IN OLDER ADULTS

老年人的药物遗传学和治疗反应

• 批准号: 6169084
• 负责人: SUSAN R HECKBERT
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6169084
• 关键词: ACE inhibitors; angiotensin II; angiotensin receptor; antidepressants; antihypertensive agents; beta antiadrenergic agent; bronchodilators; calcium channel blockers; clinical research; coronary disorder; cytochrome P450; disease /disorder proneness /risk; drug adverse effect; drug metabolism; drug receptors; genetic polymorphism; genetic susceptibility; genotype; human data; human genetic material tag; human old age (65+); hypertension; membrane proteins; pharmacogenetics; respiratory function

The goal of this research is to investigate whether genetic polymorphisms in drug metabolizing enzymes, drug receptors, and drug effector pathways explain some of the variability in response to drug therapy for common conditions in older adults. Genotypes of the cytochrome P450 CYP2D6 which are associated with slow metabolizer status may confer increased susceptibility to the adverse cardiovascular effects of the beta blockers metoprolol or timolol and the tricyclic antidepressant drugs. Mutations of the beta2 adrenergic receptor may be assoicated with variations in response to bronchodilators among individuals with obstructive airways disease; and mutations of the renal tubular protein alpha-adducin or the angiotensin II type 1 receptor with variations in response to antihypertensive therapy. The proposed project will investigate the possibility that susceptibility to the toxic effects of several drugs commonly used by the elderly may be genetically determined and reside in a small proportion of the population who are slow metabolizers. It will also investigate the association of inherited variation in drug receptors and drug effector pathways with the control of obstructive airways disease and hypertension, important chronic conditions in the elderly. This application is an ancillary study to the Cardiovascular Health Study (CHS), a prospective population-based cohort study of risk factors for coronary heart disease and stroke in 5888 adults 65 years and older. Extensive information on risk factors, medications, health behaviors, laboratory and clinical measurements, and cardiovascular events are available from baseline and yearly examinations with an average of 7.5 years of follow-up by the time of this project. DNA has been prepared for 96 percent of the cohort members. The main tasks of the proposed project are: 1) identification of CHS participants who use antihypertensive, bronchodilator, and antidepressant drugs; 2) laboratory analysis of the DNA specimens to determine CYP2D6, beta2 receptor, alpha-adducin, and angiotensin II type 1 receptor genotypes, 3) measurement of plasma drug levels, and 4) data analysis of the association of genotype with clinical events, subclinical endpoints, and the control of chronic disease. This project will incorporate advances in molecular biology in the study of response to drug therapy for common conditions, with the goal of improving clinical care of the elderly.

本研究的目的是调查药物代谢酶、药物受体和药物效应途径的遗传多态性是否解释了老年人对常见疾病药物治疗反应的一些变异性。与慢代谢状态相关的细胞色素P450 CYP2D6基因型可能增加了受体阻滞剂美托洛尔或替马洛尔以及三环抗抑郁药物对心血管不良影响的易感性。β 2肾上腺素能受体的突变可能与阻塞性气道疾病患者对支气管扩张剂的反应变化有关；肾小管α -内收蛋白或血管紧张素II型1受体的突变与抗高血压治疗反应的变化。拟议的项目将调查老年人对几种常用药物的毒性作用的易感性可能是由基因决定的，并且存在于一小部分代谢缓慢的人群中。它还将研究药物受体和药物效应通路的遗传变异与控制阻塞性气道疾病和高血压（老年人的重要慢性疾病）的关系。这项应用是心血管健康研究（CHS）的辅助研究，CHS是一项基于人群的前瞻性队列研究，研究了5888名65岁及以上的成年人冠心病和中风的危险因素。关于风险因素、药物、健康行为、实验室和临床测量以及心血管事件的广泛信息可从基线和年度检查中获得，到本项目实施时平均随访7.5年。96%的队列成员的DNA已经准备好了。拟建项目的主要任务是：1)识别使用抗高血压、支气管扩张剂和抗抑郁药物的CHS参与者；2)对DNA标本进行实验室分析，确定CYP2D6、β 2受体、α -内收蛋白和血管紧张素II型1受体基因型；3)测定血浆药物水平；4)基因型与临床事件、亚临床终点和慢性疾病控制的相关性数据分析。该项目将结合分子生物学的进展，研究常见疾病对药物治疗的反应，目的是改善老年人的临床护理。