Published Online
on April 1, 2002

A more recent version of this article appeared on April 23, 2002

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Submitted on November 26, 2001
Revised on February 12, 2002
Accepted on February 14, 2002

Angiotensinogen Genotype Affects Renal and Adrenal Responses to Angiotensin II in Essential Hypertension

Paul N. Hopkins MD, MSPH^*, Steven C. Hunt PhD, Xavier Jeunemaitre MD, PhD, Barbara Smith LPN, Daniel Solorio BS, Naomi D.L. Fisher MD, Norman K. Hollenberg MD, PhD, and Gordon H. Williams MD

From Cardiovascular Genetics, Cardiology Division, University of Utah, Salt Lake City (P.N.H., S.C.H., B.S., D.S.); Laboratoire de Génétique Moléculaire, Hôpital Européen Georges Pompidou, Paris, France (X.J.); and the Endocrine-Hypertension Division, Department of Medicine, and Department of Radiology, Harvard Medical School and Brigham and Women's Hospital, Boston, Mass (N.D.L.F., N.K.H., G.H.W.).

^* To whom correspondence should be addressed. E-mail: paul{at}ucvg.med.utah.edu.

Background—Renovascular and adrenal responses to infused angiotensin II (Ang II) are intermediate phenotypes that may indirectly reflect tissue renin-angiotensin system activity. We examine herein angiotensinogen (AGT) as a candidate gene to help elucidate potential mechanisms for previously reported AGT linkage and association studies.

Methods and Results—Renal plasma flow and plasma aldosterone were measured before and after a 45-minute infusion of Ang II (3 ng · kg^-1 · min^-1) in 190 hypertensive patients who were on carefully controlled high- and low-salt diets. Reduced renal vascular (P=0.0002) and adrenal (P=0.002) responses to infused exogenous Ang II were associated with the AGT -6A allele. In multiple logistic regression, greater body mass index, lower basal renal plasma flow, and higher diastolic blood pressure together with AGT -6A genotype were associated with lower renal vascular response. In contrast, only male sex and AGT -6A genotype were associated with lower adrenal response. When both the renal and adrenal responses to Ang II were in the lowest tertile, the AGT -6AA genotype was present in 55.6%; in contrast, when both responses were in the upper 2 tertiles, the -6AA genotype was present in only 17.8% (P=0.001).

Conclusions—A clear association between AGT genotype and response to infused Ang II was demonstrated for both the renal vasculature and the adrenal, consistent with the hypothesis that the AGT -6A genotype results in increased tissue expression of angiotensinogen and Ang II.

Key words: angiotensin • genetics • hypertension • kidney • renin

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