This is one of four collaborative R01s, representing the University of Minnesota, for the competitive renewal of the Genetics of Hypertension Associated Treatments (GenHAT) study. The goal of this competitive renewal is to comprehensively evaluate the pharmacogenetic basis of antihypertensive treatment response using state-of-the-art methods. There is large between-person variation in response to drugs, and genetic variation contributes to variable treatment response. To determine if genetic variants interact with antihypertensive medications to modify the risk of fatal coronary heart disease and non-fatal myocardial infarction and other cardiovascular disease outcomes in high-risk hypertensive adults. GenHAT is an ancillary study to ALLHAT, a randomized trial of four antihypertensive treatments (chlorthalidone, amlodipine, lisinopri and doxazosin) conducted in 42,418 high-risk hypertensive patients who were followed an average of 4.9 years (3.2 years for the truncated doxazosin arm). Using a case-cohort design, in Aim 1 we will examine whether single SNPs (both htSNPs and nonsynonomous SNPs) within genes in candidate-gene pathways of relevance for the ALLHAT medications (e.g., the renin-angiotensin-aldosterone system, the sodium homeostasis pathway, the endothelial system, and lipid and diabetes pathways) interact with antihypertensive treatments to modify risk of fatal and non-fatal coronary heart disease or stroke, heart failure, peripheral arterial disease, end state renal disease and all-cause mortality. We will genotype 96 ancestry-informative markers on all cases and the cohort random sample and use structured association testing (SAT) methods to control for potential population stratification. We will implement false discovery rate (FDR) methods to take multiple testing into account. For Aim 2 we will examine whether multiple SNPs in multiple genes within selected candidate-gene pathways interact with antihypertensive treatments to modify risk of CHD and other outcomes, as outlined for Aim 1. SAT and FDR methods will also be used for Aim 2 to control for population stratification and multiple testing. Finally, Aim 3 will enhance the overall utility of GenHAT data to the scientific community by establishing a mechanism for external investigators to undertake genetic analysis within GenHAT for 20 genetic variants for the case-cohort sample. GenHAT offers an unparalleled opportunity to determine the pharmacogenetic basis of antihypertensive treatment.