(Circulation. 1995;92:2381-2384.)
© 1995 American Heart Association, Inc.
Articles |
Genetic Linkage of the ACE Gene to Plasma Angiotensin-Converting Enzyme Activity but Not to Blood Pressure
A Quantitative Trait Locus Confers Identical Complex Phenotypes in Human and Rat Hypertension
From the Cardiovascular Division, Department of Medicine, Brigham & Women's Hospital, the Department of Cardiology, Children's Hospital, Harvard Medical School, and the Division on Biological Sciences, Harvard School of Public Health, Boston, Mass (R.K., N.H., K.L.); and the Max Delbrück Centre for Molecular Medicine (D.G.), Berlin, Germany.
Correspondence to Klaus Lindpaintner, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Thorn 1103, Boston, MA 02115. E-mail kl@calvin.bwh.harvard.edu.
Background An allelic variant of the ACE gene has been found to be linked to plasma angiotensin-converting enzyme (ACE) activity in humans and has been implicated in the etiology of some common cardiovascular disorders. Previously, we have shown significant genetic linkage of blood pressure to a region on rat chromosome 10 that contains ACE in an experimental F2-intercross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and the normotensive Wistar-Kyoto (WKYHD-0) reference strain. Subsequent investigations revealed marked differences in plasma ACE activity among the SHRSPHD and WKYHD-0 strains. Nonetheless, the physiological relevance of these findings remained obscure. We therefore investigated the genetic determination of plasma ACE activity and its relation to blood pressure and dietary NaCl exposure in a model of experimental genetic hypertension, the SHRSPHD.
Methods and Results We conducted a further crossbreeding experiment between SHRSPHD and a congenic reference strain, WKYHD-1, that carries a 6-centimorgan (cM) long, SHRSP-homologous segment introgressed in chromosome 10, 26 cM remote from ACE. This allowed us to contrast effects on blood pressure and ACE activity conferred by the ACE locus with other more remote loci within the congenic chromosomal region. Genetic analysis in this F2 (WKYHD-1xSHRSPHD) cross revealed that plasma ACE activity was determined almost entirely by genetic effects of the ACE gene locus (lod score=43). However, neither plasma ACE nor the ACE locus showed any cosegregation with blood pressure before or after dietary NaCl exposure.
Conclusions These results demonstrate that a molecular variant of the ACE gene determines plasma ACE activity but exhibits no direct effect on blood pressure. Moreover, the findings also exclude the possibility that plasma ACE is secondarily affected by blood pressure or excess dietary NaCl exposure. Our results reconcile the previous discrepancy between findings in human and experimental hypertension.
Key Words: hypertension • genes • angiotensin • enzymes
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