The Genetics of Hypertension Associated Treatments (GenHAT) is proposed as a prospective study to examine whether the association between selected hypertensive genes and combined fatal coronary heart disease and nonfatal myocardial infarction in high-risk hypertensives is modified by the type of antihypertensive treatment, leading to differential risks of coronary heart disease (CHD). Such gene-treatment interactions might shed important light On the variation in patient response to antihypertensive agents, and improve our ability to pick the right antihypertensive for specific patients. GenHAT will be an ancillary study to ALLHAT (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). ALLHAT recruited 42,515 hypertensives and randomized them to one of four antihypertensive agents (lisinopril, chlorthalidone, amlodipine, and doxazosin); follow-up will be completed in March, 2002. GenHAT will characterize hypertension genetic variants and determine their interaction with antihypertensive treatments in relation to CHD. DNA from frozen clots stored at the ALLHAT Central Laboratory will be used to genotype variants of hypertension genes (angiotensinogen -6, angiotensin converting enzyme insertion/deletion, angiotensin type- 1 receptor, alpha-adducin, beta2 adrenergic receptor, lipoprotein lipase, and 10 new hypertension variants expected to be discovered during the course of the study). In addition to the primary aim, a number of secondary aims will be undertaken to evaluate gene- treatment interactions in relation to other endpoints, including all-cause mortality, stroke, heart failure, left ventricular hypertrophy, decreased renal function, peripheral arterial disease, and blood pressure lowering. Because of the ethnic and gender diversity of ALLHAT, we will also assess effects of these variants on outcomes in key subgroups (age >65 years, women, African Americans, Type II diabetics), and whether the gene-treatment interactions in relation to outcomes are consistent across subgroups. This proposal has the advantages of (1) incorporation into an already funded clinical trial, and (2) collaboration with experienced investigators in genetic analysis (Drs. Boerwinkle and Eckfeldt) and clinical trials (Drs. Davis and Ford). It will, therefore, provide an important and cost-efficient contribution to the knowledge and understanding of the treatment of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063082-04
Application #
6527408
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M2))
Program Officer
Nwachuku, Chuke
Project Start
1999-09-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$1,216,653
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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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