Variants Of Renin-angiotensin System Research Articles

Influence of ACE gene on differential response to sertraline versus fluoxetine in patients with major depression: a randomized controlled trial.

Extensive distribution of the different components of renin angiotensin system (RAS) in the brain, along with their roles in promoting anxiety, depression and brain inflammation, opposes RAS as a potential therapeutic target in major depression. Actions of angiotensin II, the main product of RAS, are reduced by antidepressants and this signifies the complex interplay of different mechanisms involved in response to therapy. Here, we hypothesized that genetic polymorphisms of RAS may affect the outcome of therapy in depressed patients. The frequencies of variants of genes encoding for angiotensin-converting enzyme (ACE) insertion/deletion (I/D), rs4291 and rs4343 polymorphisms were determined in extracted DNAs of 200 newly diagnosed depressed patients. Patients were randomly divided into two groups, one treated with fluoxetine and the other treated with sertraline for 12weeks. Responsive patients were determined by psychiatrist using Hamilton questionnaire and were compared with regard to their genetic variants. Carriers of the D allele and patients with DD genotype responded significantly better to sertraline than to fluoxetine (P=0.0006, odds ratio (OR)=3.0, 95% confidence interval (CI)=1.80-5.08; P=0.006, OR=3.7, 95% CI=1.66-8.29, respectively). Mutant genotypes (GG and TT) of rs4343 and rs4291 polymorphisms were also more frequent in patients responding to sertraline, though not achieving the significance level (P=0.162 and P=0.256, respectively). These findings suggest that special genetic variants of RAS may influence or be an indicator for better response to sertraline.

Genetic variant of the renin-angiotensin system and prevalence of type 2 diabetes mellitus: a modest but significant effect of aldosterone synthase

Recent genome-wide association studies have identified multiple variants that confer risk of type 2 diabetes mellitus (DM). However, established associations explain only a part of the heritability. Thus, even at the genome-wide association studies era, candidate gene approach should be still useful. Recent interventional studies against the renin-angiotensin system (RAS) showed reduction in new onset of DM, implying the system is involved in the onset. We substantiated the hypothesis that genetic variants of RAS have significant association with prevalence of DM. We enrolled to the study consecutive 782 subjects who had consulted our hospitals for mainly lifestyle related diseases. They consisted of 282 (36.1 %) diabetes cases. Genotypes were assayed with genomic DNA for conventional four genes of the RAS, i.e., angiotensin converting enzyme (ACE) insertion/deletion variant, angiotensinogen (AGT) M235T variant, angiotensin II type I receptor (AT1) A1166C variant, and aldosterone synthase (CYP11B2) C-344T variant. Association between the genetic variants of the RAS and prevalence of type 2 DM was tested. A significant association of DM and CYP11B2 genotype was obtained. There was no significant association between DM and ACE, AGT and AT1 variants. A multivariate logistic regression showed that age, gender, and CYP11B2 genotype were independent factors for association to diabetes, the DM risk of CC/CT to TT being 1.40 (95 % CI 1.04–1.90, p = 0.029). Thus, it is concluded that a genetic variant of the RAS should have a modest but significant impact on the onset of type 2 diabetes mellitus.

Gene Polymorphism of Angiotensin II Type 1 and Type 2 Receptors

Renin-angiotensin system (RAS) plays a key role in pathogenesis of cardiovascular disease and in the responsiveness for various types of medications. A large number of genetic investigations have been carried out to examine the association between gene variants of RAS and predisposition to cardiovascular diseases, such as hypertension, coronary artery disease and stroke. Even though the major results were obtained from genetic association studies of angiotensinogen or angiotensin converting enzyme, unique findings were also elucidated from investigations concerning single nucleotide polymorphisms (SNPs) of 2 types of angioteinsin II receptor genes denoted as AGTR1 and AGTR2. Both genes have many SNPs in the coding and its flanking regions but most of the studies used A1166C polymorphism of AGTR1 and G1675A polymorphism of AGTR2. In the subjects with C1166 allele of AGTR1, several investigations reported increased risk for coronary artery disease, ischemic stroke, heart failure and end-stage renal disease but not for hypertension. Interestingly, a few papers pointed out the possibility that A1166C modulates the efficacy of RAS inhibitors. In the genetic analysis of AGTR2, G1675 allele carriers had increased risk for left ventricular hypertrophy, renal insufficiency and modulated hemodynamic response to RAS inhibitors. In this review, we summarized previous investigations concerning the genetic aspects of AGTR1 and AGTR2 to consider the clinical utility of SNPs of these receptors.

Identification of RAS genotypes that modulate blood pressure change by outdoor temperature

The aim of this study was to evaluate the role of polymorphisms of renin-angiotensin system (RAS) genes in modulating outdoor temperature-related blood pressure (BP) responses. Data for RAS gene polymorphisms, BP and outdoor temperature were collected from 4903 subjects from February 2003 to August 2004. Generalized additive and linear models were used to determine whether genetic variants of RAS affected the interplay between outdoor temperature and BP. Outdoor temperature (°C) was inversely associated with systolic BP and diastolic BP. These inverse relationships were stronger in subjects with ACE DD, AGT TT and AGTR1 AA genotypes. In contrast, significant positive temperature-dependent BP responses were found at temperatures above 21.4 °C in subjects with the AGTR1 C allele, but not at temperatures below 21.4 °C. Our findings suggest that subjects with ACE DD, AGT TT or AGTR1 AA genotypes are susceptible to cold temperature-induced BP increase, whereas subjects with AGTR1 C allele have a high risk of BP elevation when exposed to hot temperatures.

Candidate Gene Polymorphisms of Renin Angiotensin System and Essential Hypertension in a South Indian Tamilian Population

Genetic variants of renin angiotensin system (RAS) gene play a significant role in the pathogenesis of essential hypertension and cardiovascular diseases. In the present study, we investigated the association of RAS gene polymorphisms with hypertension by analyzing the polymorphisms ACE ID, AGT T207M, M268T and AGT1R A1166C in 462 hypertensive patients and 444 healthy subjects. Genotyping was determined by allele specific PCR, PCR-RFLP and RT-PCR Taqman assay. The ACE ID heterozygous (OR=1.5: 95% CI: 1.0-2.3, p<0.05) and ACE DD homozygous genotype (OR=1.7: 95% CI: 1.2- 2.8, p<0.01) was found to be significantly associated with hypertension. There was no significant association between AGT T207M, M268T and AGT1R A1166C gene polymorphisms and hypertension. Gender-specific analysis showed ACE ID heterozygous genotypes were positively associated with hypertension among male hypertensives (OR=1.9: 95% CI: 1.1-2.6, p<0.01). Significant gene-gene interaction was observed between ACE ID and AGT M268T polymorphisms (OR=2.0; 95% CI: 1.2-3.5, p<0.01). Our results suggest that ACE ID polymorphism is associated with hypertension. Further, gene-gene interaction between ACE ID and AGT M268T gene polymorphisms further modified the risk of essential hypertension.

Effects of Angiotensin II Type 1 Receptor Gene Polymorphisms on Insulin Resistance in a Japanese General Population: The Tanno-Sobetsu Study

Although gene polymorphisms in the renin-angiotensin system (RAS) are predisposing factors for cardiovascular diseases, the precise mechanisms and interactions among confounding factors have not been clarified. We investigated whether genetic variants of RAS are involved in insulin sensitivity in a Japanese general population. During a medical checkup in 2001, participants (n=550) were recruited from among the residents of the towns of Tanno and Sobetsu, and written informed consent was obtained to participate in the genetic analysis and the epidemiological study. The insertion/deletion (lID) polymorphism of the angiotensin-converting enzyme gene (ACE), the Met235Thr polymorphism of the angiotensinogen gene (AGT), and the A1166C polymorphism of the angiotensin II type 1 receptor gene (AGTR1) were determined by gel electrophoresis or the TaqMan PCR method. We assessed insulin sensitivity using the homeostasis model assessment insulin resistance (HOMA-IR). The RAS gene polymorphisms were not associated with log-transformed values of HOMA-IR, whereas borderline association (p=0.02) was found between the A1166C polymorphism and dichotomous categorization of insulin resistance (defined as HOMA-IR > or =1.73). Our results suggested that the A1166C polymorphism of AGTR1 might affect insulin resistance by altering the responsiveness to angiotensin II signaling, though this mechanism is as yet inconclusive. Further study is required to confirm these findings in a larger, multi-ethnic population.