PHARMACOGENETICS AND RESPONSE TO THERAPY IN OLDER ADULTS

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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.