Despite availability of multiple antihypertensive drugs, which act on a variety of blood pressure-regulating systems, less than 40 percent of treated hypertensive patients have their blood pressures controlled. The overall objective of this research program is to elucidate the genetic basis of interindividual variation in responses to antihypertensive drug therapies. Such knowledge may reveal molecular mechanisms contributing to hypertension and aid in the tailoring of more effective antihypertensive drug therapy in individual patients. Blood pressure response to a thiazide diuretic depends on initial reduction of intravascular fluid volume due to inhibition of renal sodium reabsorption, and is subsequently opposed by counterregulatory activities of the renin-angiotensin-aldosterone system. Conversely, blood pressure response to an angiotensin H receptor blocker depends on inhibition of the renin-angiotensin-aldosterone system and is opposed by counterregulatory retention of sodium and fluid volume. In the first cycle of this project, we found that variants of the genes encoding angiotensin-converting enzyme and the G-proteins Beta3-subunit predicted blood pressure response to a thiazide diuretic in hypertensive African-Americans (n = 300) and non-Hispanic whites (n = 300).
Aim 1 of this proposed renewal application will use the already-collected samples to determine whether variation in additional genes encoding the renin-angiotensin-aldosterone system, renal sodium transport systems, or related modulators of vasoconstriction and volume predict interindividual variation in blood pressure response to a thiazide diuretic.
Aim 2 will determine whether variation in these same genes predicts interindividual variation in blood pressure response to an angiotensin II receptor blocker in newly recruited hypertensive African-Americans (n = 300) and non-Hispanic whites (n = 300).
Aim 3 will use the combined samples from aims 1 and 2 (n=600 in each racial group) to contrast the identified predictors of response between these two antihypertensive drugs that differentially target the balance of vasoconstriction and volume maintaining blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL053330-09S1
Application #
7027859
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Nwachuku, Chuke
Project Start
1997-02-01
Project End
2007-01-31
Budget Start
2005-04-19
Budget End
2006-01-31
Support Year
9
Fiscal Year
2005
Total Cost
$49,228
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Schwartz, Gary L; Bailey, Kent; Chapman, Arlene B et al. (2013) The role of plasma renin activity, age, and race in selecting effective initial drug therapy for hypertension. Am J Hypertens 26:957-64
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
Le, MyPhuong T; Lobmeyer, Maximilian T; Campbell, Marcus et al. (2013) Impact of genetic polymorphisms of SLC2A2, SLC2A5, and KHK on metabolic phenotypes in hypertensive individuals. PLoS One 8:e52062
Chai, High Seng; Chapman, Arlene B; Boerwinkle, Eric (2013) Response to genomic association analysis identifies multiple loci influencing antihypertensive response to an angiotensin II receptor blocker. Hypertension 61:e6
Turner, Stephen T; Bailey, Kent R; Schwartz, Gary L et al. (2012) Genomic association analysis identifies multiple loci influencing antihypertensive response to an angiotensin II receptor blocker. Hypertension 59:1204-11
Schwartz, Gary L (2011) Screening for adrenal-endocrine hypertension: overview of accuracy and cost-effectiveness. Endocrinol Metab Clin North Am 40:279-94, vii
Duarte, Julio D; Lobmeyer, Maximilian T; Wang, Zhiying et al. (2010) Lack of association between polymorphisms in STK39, a putative thiazide response gene, and blood pressure response to hydrochlorothiazide. Pharmacogenet Genomics 20:516-9
Chai, High-Seng; Sicotte, Hugues; Bailey, Kent R et al. (2009) GLOSSI: a method to assess the association of genetic loci-sets with complex diseases. BMC Bioinformatics 10:102
Canzanello, Vincent J; Baranco-Pryor, Evelyn; Rahbari-Oskoui, Frederic et al. (2008) Predictors of blood pressure response to the angiotensin receptor blocker candesartan in essential hypertension. Am J Hypertens 21:61-6
Fridley, Brooke L; Turner, Stephen T; Chapman, Arlene et al. (2008) Reproducibility of Genotypes as Measured by the Affymetrix GeneChip(R) 100K Human Mapping Array Set. Comput Stat Data Anal 52:5367-5374

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