PHARMACOGENETICS AND RESPONSE TO THERAPY IN OLDER ADULTS

本研究的目的是调查药物代谢酶、药物受体和药物效应通路的遗传多态性是否解释了老年人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 CYP 2D 6基因型可能增加对β受体阻滞剂美托洛尔或噻吗洛尔和三环类抗抑郁药的心血管不良反应的易感性。β 2肾上腺素能受体的突变可能与阻塞性气道疾病个体对支气管扩张剂的反应变化相关;肾小管蛋白α-内收蛋白或血管紧张素II 1型受体的突变与抗高血压治疗的反应变化相关。 拟议的项目将调查老年人对几种常用药物的毒性作用的敏感性是否可能是由遗传决定的，并存在于代谢缓慢的一小部分人口中。 它还将调查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联。本申请是心血管健康研究（CHS）的辅助研究，CHS是一项在5888名65岁及以上成人中进行的冠心病和卒中风险因素的前瞻性基于人群的队列研究。 从基线和年度检查中获得了关于风险因素、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，到本项目时平均随访7.5年。 已经为96%的队列成员准备了DNA。 本研究的主要任务是：1）识别使用抗高血压、支气管扩张和抗抑郁药物的CHS参与者; 2）DNA样本的实验室分析，以确定CYP 2D 6、β 2受体、α-内收蛋白和血管紧张素II 1型受体基因型，3）血浆药物水平的测量，和4）基因型与临床事件相关性的数据分析，亚临床终点和慢性疾病的控制。该项目将把分子生物学的进展纳入对常见疾病药物治疗反应的研究中，目的是改善老年人的临床护理。

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.