This is one of four collaborative R01s, representing the University of Alabama at Birmingham, 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 candidategene 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083498-03
Application #
7631419
Study Section
Special Emphasis Panel (ZRG1-CVS-C (60))
Program Officer
Einhorn, Paula
Project Start
2007-08-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2009
Total Cost
$726,559
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Genetics
Type
Schools of Public Health
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Lynch, A I; Irvin, M R; Boerwinkle, E et al. (2013) RYR3 gene polymorphisms and cardiovascular disease outcomes in the context of antihypertensive treatment. Pharmacogenomics J 13:330-4
Lynch, Amy I; Eckfeldt, John H; Davis, Barry R et al. (2012) Gene panels to help identify subgroups at high and low risk of coronary heart disease among those randomized to antihypertensive treatment: the GenHAT study. Pharmacogenet Genomics 22:355-66
Zhang, Xue; Lynch, Amy I; Davis, Barry R et al. (2012) Pharmacogenetic association of NOS3 variants with cardiovascular disease in patients with hypertension: the GenHAT study. PLoS One 7:e34217
Sherva, Richard; Ford, Charles E; Eckfeldt, John H et al. (2011) Pharmacogenetic effect of the stromelysin (MMP3) polymorphism on stroke risk in relation to antihypertensive treatment: the genetics of hypertension associated treatment study. Stroke 42:330-5
Tanner, Rikki M; Lynch, Amy I; Brophy, Victoria H et al. (2011) Pharmacogenetic associations of MMP9 and MMP12 variants with cardiovascular disease in patients with hypertension. PLoS One 6:e23609
Rodin, Andrei S; Gogoshin, Grigoriy; Boerwinkle, Eric (2011) Systems biology data analysis methodology in pharmacogenomics. Pharmacogenomics 12:1349-60
Irvin, Marguerite R; Lynch, Amy I; Kabagambe, Edmond K et al. (2010) Pharmacogenetic association of hypertension candidate genes with fasting glucose in the GenHAT Study. J Hypertens 28:2076-83
Lynch, Amy I; Boerwinkle, Eric; Davis, Barry R et al. (2009) Antihypertensive pharmacogenetic effect of fibrinogen-beta variant -455G>A on cardiovascular disease, end-stage renal disease, and mortality: the GenHAT study. Pharmacogenet Genomics 19:415-21
Maitland-van der Zee, Anke-Hilse; Peters, Bas J M; Lynch, Amy I et al. (2009) The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13 ) on the effectiveness of statins: the GenHAT study. Pharmacogenet Genomics 19:338-44