Objective The angiotensinogen T235 allele is associated with elevated plasma angiotensinogen levels whereas the angiotensin-converting enzyme (ACE) deletion (D) allele is associated with elevated ACE activity. It remains unclear, however, whether these genetically mediated elevations of angiotensinogen and ACE levels are functionally relevant. Given that the renin–angiotensin system is subject to renin feedback regulation, we specifically investigated the associations between the angiotensinogen T235 allele and the ACE D allele with plasma renin and prorenin levels.

Design and methods Plasma levels of renin, prorenin, angiotensinogen, ACE and aldosterone, as well as angiotensinogen and ACE genotypes were determined in 228 men and 168 women (age 52–65 years), who had participated in a population survey in southern Germany. Subjects taking antihypertensive drugs or oestrogen replacement therapy were excluded.

Results We corroborated previous findings demonstrating associations between the T235M polymorphism and plasma angiotensinogen levels (P< 0.05) and between the ACE I/D polymorphism and plasma ACE (P< 0.01). After adjustment for sex, age and blood pressure, the T235 allele of the angiotensinogen gene was also related to lower plasma prorenin (P< 0.03) and renin (P< 0.01) levels, but not to plasma ACE and aldosterone. By contrast, the ACE I/D polymorphism was not related to components of the system other than plasma ACE.

Conclusions The angiotensinogen T235 allele is associated with decreased renin levels. This finding may point to a mechanism that counteracts the genetic elevation of angiotensinogen plasma levels and, thus, the plasmatic angiotensin II-generating pathway in subjects carrying the angiotensinogen T235 allele. These results may help to explain discrepant findings regarding associations between this allele and cardiovascular disorders. Furthermore, the presumed feedback downregulation of renin levels supports the importance of angiotensinogen as a determinant of angiotensin II generation. Finally, no evidence was found suggesting that the ACE D allele affects components of the circulating renin–angiotensin system other than plasma ACE.