This is one of four collaborative R01s, representing the University of Minnesota, for the competitive renewalof the Genetics of Hypertension Associated Treatments (GenHAT) study. The goal of this competitiverenewal is to comprehensively evaluate the pharmacogenetic basis of antihypertensive treatment responseusing state-of-the-art methods. There is large between-person variation in response to drugs, and geneticvariation contributes to variable treatment response. To determine if genetic variants interact withantihypertensive medications to modify the risk of fatal coronary heart disease and non-fatal myocardialinfarction and other cardiovascular disease outcomes in high-risk hypertensive adults. GenHAT is anancillary 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 followedan average of 4.9 years (3.2 years for the truncated doxazosin arm). Using a case-cohort design, in Aim 1we will examine whether single SNPs (both htSNPs and nonsynonomous SNPs) within genes in candidate-genepathways 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 withantihypertensive treatments to modify risk of fatal and non-fatal coronary heart disease or stroke, heartfailure, peripheral arterial disease, end state renal disease and all-cause mortality. We will genotype 96ancestry-informative markers on all cases and the cohort random sample and use structured associationtesting (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 inmultiple genes within selected candidate-gene pathways interact with antihypertensive treatments to modifyrisk of CHD and other outcomes, as outlined for Aim 1. SAT and FDR methods will also be used for Aim 2 tocontrol for population stratification and multiple testing. Finally, Aim 3 will enhance the overall utility ofGenHAT data to the scientific community by establishing a mechanism for external investigators toundertake genetic analysis within GenHAT for 20 genetic variants for the case-cohort sample. GenHAToffers an unparalleled opportunity to determine the pharmacogenetic basis of antihypertensive treatment.
