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

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 F-2-intercross between the stroke-prone spontaneously hypertensive rat (SHRSP(HD)) and the normotensive Wistar-Kyoto (WKYHD-0) reference strain. Subsequent investigations revealed marked differences in plasma ACE activity among the SHRSP(HP) 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 SHRSP(HD). Methods and Results We conducted a further crossbreeding experiment between SHRSP(HD) 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 F-2 (WKYHD-1xSHRSP(HD)) cross revealed that plasma ACE activity was determined almost entirely by genetic effects of the ACE gene locus(led 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.