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

Abstract

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. B max and K D values of the Ang II binding sites on platelets of each individual were calculated to examine a possible relationship between these parameters and the AT1R genotype. A highly significant association of the ACE 4656(CT) 2/3 variant with plasma ACE levels was observed (PϽ0.0001). ANOVA showed a significant effect of the AGT C-532T polymorphism on AGT plasma levels (Pϭ0.017), but no significant effect was detectable with the other AGT polymorphisms 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 (Pϭ0.02 Key Words: angiotensinogen Ⅲ angiotensin-converting enzyme Ⅲ angiotensin II Ⅲ aldosterone Ⅲ polymorphism Ⅲ blood pressure S ingle nucleotide biallelic polymorphisms are powerful tools when used to search for a linkage disequilibrium between a marker genotype and a disease, mainly of multifactorial origin. With these markers, candidate genes of the renin-angiotensin-aldosterone system (RAAS), including those of angiotensinogen (AGT), the angiotensin I-converting enzyme (ACE), and type I angiotensin (Ang) II receptor (AT1R), have been investigated in association studies with cardiovascular diseases, such as hypertension or myocardial infarction. As examples of these associations, the ACE insertion/deletion (I/D) polymorphism was found associated with myocardial infarction, cardiac hypertrophy after physical exercise, and Alzheimer disease, 1,2 and the AGT or AT1R genes were found to be associated with hypertension. 3,4 Therefore, it is of interest to establish relationships between these marker genotypes and intermediate phenotypes related to the disease and to the gene tested to understand the physiopathology of these associations, thus helping to clarify inconsistent results issued from some association studies. Among these observations, the st...

Polymorphisms of angiotensinogen and angiotensin-converting enzyme associated with lower extremity arterial disease in the Health, Aging and Body Composition study

“…4,28 Frequencies of G-6A in white participants of this study were similar to those in reports from Paillard et al 29 and Tang et al 30 The D allele frequency of ACE in this study was similar to that in the reports from a meta-analysis of 145 studies, 31 except for no significantly racial difference in our study. In addition to the genetic variation, a significant difference in vascular health between black and white elderly people in this study was also found to be consistent with most of the previous studies.…”

Renin–angiotensin system gene polymorphisms predict the progression to renal insufficiency among Asians with lupus nephritis

“…The D allele is known to correlate with increased tissue 15 and serum ACE levels in a dose-dependent manner in various ethnic groups. [16][17][18][19] The (CT) 2 polymorphism was shown to correlate with serum ACE in French and Nigerian populations. 16,19 We also examined two Atg polymorphisms, M235T (C to T transition at position 4072) and C-532T (C to T transition in 5 0 -flanking region).…”

“…[16][17][18][19] The (CT) 2 polymorphism was shown to correlate with serum ACE in French and Nigerian populations. 16,19 We also examined two Atg polymorphisms, M235T (C to T transition at position 4072) and C-532T (C to T transition in 5 0 -flanking region). The M235T T allele is correlated in an allelic dose-dependent manner with Atg tissue levels 20 and with increased serum levels in various ethnic groups.…”

Context-dependency of the relation between left ventricular mass and AGT gene variants

“…Genotyping of the study population for the two diallelic polymorphisms in the 5 0 -flanking region (CÀ532T, GÀ6A) of the AGT gene was performed by hybridization of PCR products using allele specific oligonucleotides as described by Paillard et al 15 …”