Abstract

Essential hypertension (hypertension) is a common disorder that contributes to morbidity, mortality, and cost of health care, especially among African-Americans. Despite availability of multiple antihypertensive drugs, acting on a variety of blood pressure (BP)-regulating systems, less than 40% of treated patients achieve BP control. The overall objective of this application is to advance beyond selected candidate gene studies to entire genome assessment for as yet unknown genes influencing antihypertensive drug responses. By identifying novel drug-response genes, the proposed pharmacogenomic study has the potential to enable more effective tailoring of antihypertensive therapy in individual patients. The Genetic Epidemiology of Responses to Antihypertensives (GERA) study (R01 HL 53330) is identifying candidate gene polymorphisms of the renin-angiotensin-aldosterone system and renal sodium transport systems that predict BP responses to a thiazide diuretic (protocol 1) and to an angiotensin II receptor blocker (protocol 2) in community-based hypertensive African-Americans and non-Hispanic whites. However, explaining sufficient variation in BP responses to be clinically useful requires a global, pharmacogenomic approach. Accordingly, measurements of antihypertensive drug responses and stored DNA from GERA will be used to accomplish the following specific aims:
Aim 1 : Use genome-wide association analyses of single nucleotide polymorphisms to identify novel genes influencing BP response to a thiazide diuretic in hypertensive African-Americans (n = 200) and non-Hispanic whites (n = 200) previously enrolled in GERA protocol 1.
Aim 2 : Use genome-wide association analyses of single nucleotide polymorphisms to identify novel genes influencing BP response to an angiotensin II receptor blocker in hypertensive African-Americans (n = 200) and non-Hispanic whites (n = 200) enrolled in GERA protocol 2.
Aim 3 : Determine whether genomic variations associated with BP response to a thiazide diuretic differ from those associated with BP response to an angiotensin II receptor blocker in the combined samples of 400 hypertensive African-Americans and 400 non-Hispanic whites from aims 1 and 2.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074735-03
Application #
6942959
Study Section
Special Emphasis Panel (ZHL1-CSR-G (S1))
Program Officer
Bookman, Ebony B
Project Start
2003-09-26
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2005
Total Cost
$859,934
Indirect Cost

  Institution

Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905

  Publications

Hiltunen, Timo P; Donner, Kati M; Sarin, Antti-Pekka et al. (2015) Pharmacogenomics of hypertension: a genome?wide, placebo?controlled cross?over study, using four classes of antihypertensive drugs. J Am Heart Assoc 4:e001521
Del-Aguila, J L; Cooper-DeHoff, R M; Chapman, A B et al. (2015) Transethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide. Pharmacogenomics J 15:153-7
Del-Aguila, J L; Beitelshees, A L; Cooper-Dehoff, R M et al. (2014) Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J 14:35-40
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
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
Duarte, Julio D; Zineh, Issam; Burkley, Ben et al. (2012) Effects of genetic variation in H3K79 methylation regulatory genes on clinical blood pressure and blood pressure response to hydrochlorothiazide. J Transl Med 10:56
Peng, Gang; Luo, Li; Siu, Hoicheong et al. (2010) Gene and pathway-based second-wave analysis of genome-wide association studies. Eur J Hum Genet 18:111-7
Dong, Hua; Siu, Hoicheong; Luo, Li et al. (2010) Investigation gene and microRNA expression in glioblastoma. BMC Genomics 11 Suppl 3:S16
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
Rodin, Andrei S; Litvinenko, Anatoliy; Klos, Kathy et al. (2009) Use of wrapper algorithms coupled with a random forests classifier for variable selection in large-scale genomic association studies. J Comput Biol 16:1705-18

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