? 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 #
5R01HL063082-08
Application #
7471517
Study Section
Special Emphasis Panel (ZRG1-CVS-C (60))
Program Officer
Einhorn, Paula
Project Start
1999-09-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
8
Fiscal Year
2008
Total Cost
$253,750
Indirect Cost
Name
University of Alabama Birmingham
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Do, A N; Lynch, A I; Claas, S A et al. (2016) The effects of genes implicated in cardiovascular disease on blood pressure response to treatment among treatment-naive hypertensive African Americans in the GenHAT study. J Hum Hypertens 30:549-54
Bis, Joshua C; Sitlani, Colleen; Irvin, Ryan et al. (2015) Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. PLoS One 10:e0140496
Sørensen, Izel F; Vazquez, Ana I; Irvin, Marguerite R et al. (2014) Pharmacogenetic effects of 'candidate gene complexes' on stroke in the GenHAT study. Pharmacogenet Genomics 24:556-63
Do, Anh N; Irvin, Marguerite R; Lynch, Amy I et al. (2014) The effects of angiotensinogen gene polymorphisms on cardiovascular disease outcomes during antihypertensive treatment in the GenHAT study. Front Pharmacol 5:210
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; Irvin, Marguerite R; Davis, Barry R et al. (2013) Genetic and Adverse Health Outcome Associations with Treatment Resistant Hypertension in GenHAT. Int J Hypertens 2013:578578
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

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