Genotype-Phenotype Relationships for the Renin-Angiotensin-Aldosterone System in a Normal Population

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Abstract
—The renin-angiotensin-aldosterone system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. The purpose of the present study was to search for associations of single nucleotide polymorphisms on 3 major candidate genes of this system with the plasma concentrations of the corresponding renin-angiotensin-aldosterone system components considered as quantitative phenotypes. Genotyping was performed in 114 normotensive subjects for different variants of the angiotensinogen (AGT) gene (C-532T, G-6A, M235T), the angiotensin I–converting enzyme (ACE) gene [4656(CT)2/3], the aldosterone synthase (CYP11B2), and the type 1 angiotensin II receptor (AT1R) gene (A1166C) by hybridization with allele-specific oligonucleotides (ASO) or enzymatic digestion of polymerase chain reaction products. Plasma levels of AGT, ACE, angiotensin II (Ang II), aldosterone, and immunoreactive active renin were measured according to standard techniques. Platelet binding sites for Ang II were analyzed by the binding of radioiodinated Ang II to purified platelets. BmaxandKDvalues of the Ang II binding sites on platelets of each individual were calculated to examine a possible relationship between these parameters and theAT1Rgenotype. A highly significant association of theACE4656(CT)2/3variant with plasma ACE levels was observed (PAGTC-532T polymorphism on AGT plasma levels (P=0.017), but no significant effect was detectable with the otherAGTpolymorphisms tested, such as the G-6A or the M235T. A significant effect association was also found between the C-344T polymorphism of the CYP11B2 gene and plasma aldosterone levels, with the T allele associated with higher levels (P=0.02). No genotype effect of theAT1RA1166C polymorphism was detected either on the Bmaxor theKDvalue of the Ang II receptors on platelets.