Career Development: The objective of this K-23 Career Development Award application is to prepare the candidate for a career as an independent patient oriented researcher. The applicant's primary area of interest is in attenuating the adverse metabolic effects associated with antihypertensive therapy in patients with metabolic syndrome by identifying pharmacologic and pharmacogenomic combinations that maximize insulin sensitivity. The University of Florida has the resources to provide the applicant with the ideal setting to examine both the clinical and pharmacogenomic aspects of insulin resistance in the setting of antihypertensive therapy. The proposed career development plan incorporates a structured didactic program focused in epidemiology, which will result in a master's degree in epidemiology via the K30 program. Additionally, the applicant will participate in seminars, conferences and focused laboratory based research tutorials conducted by experts in the field of pharmacogenomics, epidemiology and glucose homeostasis in the setting of metabolic syndrome. Clinical and Laboratory Investigations. Patients with metabolic syndrome, characterized primarily by insulin resistance are at increased risk of developing diabetes and often have hypertension (HTN). Thiazide diuretics are recommended for treating HTN in patients with metabolic syndrome, despite being associated with metabolic disturbances that result in increased insulin resistance. The major hypothesis of this study is that in patients with metabolic syndrome and HTN, blockade of the renin-angiotensin system (RAS) with an angiotensin converting enzyme (ACE) inhibitor attenuates the adverse metabolic effects of a thiazide diuretic.
Specific aims are designed to investigate whether this attenuation occurs after the addition of ACE inhibitor to diuretic and/or as a consequence of pretreatment with an ACE inhibitor. Also, laboratory based pharmacogenomic investigations will be conducted in a separate cohort of 6000 hypertensive CAD patients to identify polymorphisms associated with diabetes in the ACE, ADD1 and KCNJ1 genes, selected on the basis of their critical role in ACE inhibitor and diuretic response. This research seeks to overcome gaps in knowledge regarding the metabolic impact of antihypertensive drugs in patients with metabolic syndrome and will provide data to influence future prescribing patterns. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23HL086558-01
Application #
7178013
Study Section
Special Emphasis Panel (ZHL1-CSR-R (O1))
Program Officer
Scott, Jane
Project Start
2007-02-01
Project End
2012-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
1
Fiscal Year
2007
Total Cost
$138,202
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Weng, Liming; Quinlivan, Eoin; Gong, Yan et al. (2015) Association of branched and aromatic amino acids levels with metabolic syndrome and impaired fasting glucose in hypertensive patients. Metab Syndr Relat Disord 13:195-202
Moore, Mariellen J; Gong, Yan; Hou, Wei et al. (2014) Predictors for glucose change in hypertensive participants following short-term treatment with atenolol or hydrochlorothiazide. Pharmacotherapy 34:1132-40
Gong, Yan; McDonough, Caitrin W; Beitelshees, Amber L et al. (2014) PROX1 gene variant is associated with fasting glucose change after antihypertensive treatment. Pharmacotherapy 34:123-30
Cooper-Dehoff, Rhonda M; Hou, Wei; Weng, Liming et al. (2014) Is diabetes mellitus-linked amino acid signature associated with ?-blocker-induced impaired fasting glucose? Circ Cardiovasc Genet 7:199-205
Karnes, Jason H; Gong, Yan; Arwood, Meghan J et al. (2014) Alteration in fasting glucose after prolonged treatment with a thiazide diuretic. Diabetes Res Clin Pract 104:363-9
Smith, Steven M; Gong, Yan; Handberg, Eileen et al. (2014) Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension. J Hypertens 32:635-43
Duarte, J D; Turner, S T; Tran, B et al. (2013) Association of chromosome 12 locus with antihypertensive response to hydrochlorothiazide may involve differential YEATS4 expression. Pharmacogenomics J 13:257-63
Turner, Stephen T; Boerwinkle, Eric; O'Connell, Jeffrey R et al. (2013) Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide. Hypertension 62:391-7
Karnes, Jason H; Gong, Yan; Pacanowski, Michael A et al. (2013) Impact of TCF7L2 single nucleotide polymorphisms on hydrochlorothiazide-induced diabetes. Pharmacogenet Genomics 23:697-705
Cooper--DeHoff, Rhonda M; Bird, Steven T; Nichols, Gregory A et al. (2013) Antihypertensive drug class interactions and risk for incident diabetes: a nested case-control study. J Am Heart Assoc 2:e000125

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