The applicant seeks to enhance his research skills in the area of human hypertension and genetic epidemiology through a career development plan which includes patient-oriented research, laboratory activities, and an educational component primarily designed to develop his skills in the genetic analysis of complex traits. The proposed studies will be conducted on the General Clinical Research Center at Vanderbilt University Medical Center, an environment fully equipped for human studies. As a member of the Program in Human Genetics, the candidate will have full access to core facilities for genotyping and genetic analysis. Research: Genetic variation in the renin-angiotensin-aldosterone system (RAAS) contributes to the development of hypertension and cardiovascular and renal morbidity, complications more prevalent in African Americans that other ethnic groups. Accumulating data suggest that aldosterone plays a role in vascular toxicity independent of angiotensin (Ang) II. CYP11B2, also known as aldosterone synthase, is a focal point of aldosterone regulation. A common diallelic (C/T) polymorphism at position -344 in the promoter of CYP11B2 has been associated with increased basal and ACTH-stimulated aldosterone synthesis and hypertension in studies done in Caucasians. Independent of Ang II, increased plasma aldosterone has been associated with decreased vascular reactivity. The significance of CYP11B2 genetic variation in African Americans is not known. The central hypothesis of this proposal is that genetic variation in CYP11B2 is associated with increased aldosterone synthesis which contributes to altered vascular reactivity, endothelial dysfunction and hypertension in African Americans and Caucasians. To test this hypothesis, studies are proposed in humans to determine the effect of genetic variation in CYP11B2 on (1) the increase in aldosterone synthesis in response to Ang II and potassium, (2) vascular responsiveness to vasodilation, and (3) hypertension in African Americans. Establishing CYP11B2 -344C/T as a genetic susceptibility factor can lead to targeted therapies to reduce the incidence of hypertension and its morbidity. Through the studies proposed in this mentored award, the Candidate will gain skills in the design and implementation of human studies that have physiologic and genetic relevance to hypertension and vascular disease.
| Gainer, James V; Lipkowitz, Michael S; Yu, Chang et al. (2008) Association of a CYP4A11 variant and blood pressure in black men. J Am Soc Nephrol 19:1606-12 |
| Laffer, Cheryl L; Gainer, James V; Waterman, Michael R et al. (2008) The T8590C polymorphism of CYP4A11 and 20-hydroxyeicosatetraenoic acid in essential hypertension. Hypertension 51:767-72 |
| Gainer, James V; Bellamine, Aouatef; Dawson, Elliott P et al. (2005) Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension. Circulation 111:63-9 |
| Rosenbaum, David A; Pretorius, Mias; Gainer, James V et al. (2002) Ethnicity affects vasodilation, but not endothelial tissue plasminogen activator release, in response to bradykinin. Arterioscler Thromb Vasc Biol 22:1023-8 |
| Wilsdorf, T; Gainer, J V; Murphey, L J et al. (2001) Angiotensin-(1-7) does not affect vasodilator or TPA responses to bradykinin in human forearm. Hypertension 37:1136-40 |
