Anthipertensive PharmacoGenomics

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DESCRIPTION (provided by applicant): Essential hypertension (hypertension) is a common disorder that contributes to morbidity, mortality, and cost of health care, especially among African-Americans. Despite availability of multiple antihypertensive drugs, acting on a variety of blood pressure (BP)-regulating systems, less than 40% of treated patients achieve BP control. The overall objective of this application is to advance beyond selected candidate gene studies to entire genome assessment for as yet unknown genes influencing antihypertensive drug responses. By identifying novel drug-response genes, the proposed pharmacogenomic study has the potential to enable more effective tailoring of antihypertensive therapy in individual patients. The Genetic Epidemiology of Responses to Antihypertensives (GERA) study (R01 HL 53330) is identifying candidate gene polymorphisms of the renin-angiotensin-aldosterone system and renal sodium transport systems that predict BP responses to a thiazide diuretic (protocol 1) and to an angiotensin II receptor blocker (protocol 2) in community-based hypertensive African-Americans and non-Hispanic whites. However, explaining sufficient variation in BP responses to be clinically useful requires a global, pharmacogenomic approach. Accordingly, measurements of antihypertensive drug responses and stored DNA from GERA will be used to accomplish the following specific aims: Aim 1: Use genome-wide association analyses of single nucleotide polymorphisms to identify novel genes influencing BP response to a thiazide diuretic in hypertensive African-Americans (n = 200) and non-Hispanic whites (n = 200) previously enrolled in GERA protocol 1. Aim 2: Use genome-wide association analyses of single nucleotide polymorphisms to identify novel genes influencing BP response to an angiotensin II receptor blocker in hypertensive African-Americans (n = 200) and non-Hispanic whites (n = 200) enrolled in GERA protocol 2. Aim 3: Determine whether genomic variations associated with BP response to a thiazide diuretic differ from those associated with BP response to an angiotensin II receptor blocker in the combined samples of 400 hypertensive African-Americans and 400 non-Hispanic whites from aims 1 and 2.