Renin-angiotensin System Gene Polymorphisms Research Articles

Renin–angiotensin system genetic polymorphisms: Lack of association with CRP levels in patients with coronary artery disease

Angiotensin (Ang) II is believed to be a potential pro-inflammatory factor. The capability of Ang II to stimulate C-reactive protein (CRP) production has recently been described. Genetic polymorphisms of renin angiotensin system (RAS) components have been described to be associated with the development of coronary artery disease (CAD). This study investigated the association between six different genetic polymorphisms of RAS and serum CRP levels in a sample of CAD patients. Genotyping of RAS genes polymorphisms in 176 patients with documented CAD was performed by a modified polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Measurement of high-sensitivity (hs)-CRP was performed using standard immunoturbidimetric methods. Results show no significant differences in serum CRP regarding different variants of the six polymorphisms studied (p = 0.41, 0.24, 0.25, 0.19, 0.29, and 0.05 for Ang-converting enzyme (ACE) insertion/deletion (I/D), A-240T and A2350G, angiotensinogen M235T, AT1 receptor A1166C, and AT2 receptor C3123A polymorphisms, respectively). In conclusion, genetic polymorphisms of RAS are not associated with increased serum CRP in CAD. Compensation of an increased activity of ACE through counter-regulation and the secretion of CRP under the influence of Ang II in the vessel being local could explain the lack of association between the studied polymorphisms and CRP levels in CAD patients.

RAS Gene Polymorphisms and Renal Responsiveness to RAS Inhibition Therapy in Type 2 Diabetic Asian Indians

Objective: Inhibitors of renin angiotensin system (RAS), ACE inhibitors (ACEI) and angiotensin II receptor blockers (ARBs), are frequently used as renal-protective agents in type 2 diabetes (T2D). However, there is significant inter individual variability in response to these drugs. In the present study, we examined the role of genetic polymorphisms in ACE, AGT and AGTR1 genes, in modulating reno-protective response to ACEI and ARB therapy in north Indian T2DM subjects, with cases having diabetic nephropathy (DN) and controls without DN. Method: 810 north Indian T2D patients treated with ACEI or ARB after diagnosis were followed up for 3 years. Percent changes in eGFR, urinary albumin excretion (UAE), serum creatinine at the end of 3 years of treatment were taken as points of renoprotective response. Result: We observed that ACE II genotype and cumulative risk score of 6 was associated with better renoprotective response to ARB (p<0.05). Conclusion: Our results suggest that ACE I/D genotypes individually and in interaction with other RAS SNPs modulate renoprotective efficacy of ACEI and ARB in T2D patients, depending on the status of proteinuria.

Association between RAS Gene Polymorphisms (ACE I/D, AGT M235T) and Henoch-Schönlein Purpura in a Turkish Population

Henoch-Schönlein purpura (HSP) is a small-vessel vasculitis of autoimmune hypersensitivity, and renin-angiotensin system (RAS) regulates vascular homeostasis and inflammation with activation of cytokine release. Thus, we aimed to investigate the association between HSP andACE I/DandAGT M235Tpolymorphisms. Genotyping was determined by allele specific PCR and PCR-RFLP. We obtained a significant difference in genotype distribution (p= 0.003) and allele frequencies (p&lt; 0.001) ofACE I/Dpolymorphism between patients and controls, while no significant association was detected in genotype distribution (p&gt; 0.05) and allele frequencies (p&gt; 0.05) of theAGT M235Tpolymorphism. Risk assessment showed significant risk for HSP in the subjects both with the ID + DD genotype (p= 0.019, OR: 2.288, 95% CI: 1.136–4.609) and D allele (OR: D vs. I: 2.0528, 95% CI: 1.3632–3.0912,p= 0.001) while no significant risk was obtained for HSP in the subjects both with the MT + TT genotype (p= 0.312, OR: 1.3905, 95% CI: 0.7326–2.6391) and T allele (OR: T vs. M: 1.065, 95% CI: 0.729–1.557,p= 0.743). Furthermore, when patients were stratified by the presence of certain systemic complications of HSP, no significant association was detected withACE I/D, andAGT M235Tpolymorphisms. Our findings suggest thatACE I/Dpolymorphism is significantly associated with HSP susceptibility.

Angiotensin-converting enzyme gene variants interact with the renin-angiotensin system pathway to confer risk and protection against type 2 diabetic retinopathy.

The angiotensin‐converting enzyme (ACE) gene has been found to be associated with pathogenesis and progression of diabetic retinopathy (DR). A recent meta‐analysis comprising 2,224 Chinese patients showed moderate evidence of a relationship between the ACE insertion/deletion (I/D) polymorphism and proliferative diabetic retinopathy (PDR)1; however, the role of other renin–angiotensin system (RAS) polymorphisms and their possible interactions with ACE I/D genotypes are less clearly defined. Thus, we investigated the association and interaction between RAS gene polymorphisms and the development and progression of DR in 1,446 north Indian type 2 diabetic patients. DR patients were divided into two groups, non‐proliferative diabetic retinopathy (NPDR) and PDR. DR was diagnosed by dilating the pupils with mydriatics and then carefully examining the retina. Retinal photography or fluorescein angiography tests were also carried out. A total of 1,720 type 2 diabetic patients were screened for the presence of DR, of which, 1,446 patients were finally included for the present study. Patients receiving antihypertensive drug treatment, with any retinopathy other than DR, cataracts and cataract surgery, and age‐related macular degeneration were excluded from the study. All the participants in both the cohorts were age (≥35 years), sex and ethnicity matched. Significant deviation from the Hardy–Weinberg equilibrium of genotype distribution in the present population in ACE I/D and angiotensinogen (AGT) variant rs5050 might be a result of the moderate population size or the rare allele, which can cause a random change in allele frequencies. Furthermore, we excluded the possibility of a typing error (logarithmic odds ratio score >0). The present sample size had the power of 90% at a small effect size (0.1) and alpha level (0.05). In both the cohorts, we observed a consistently higher prevalence and increased risk of PDR in patients with the DD genotype of ACE I/D, TT genotype of AGTrs699 and the CC genotype of angiotensin II receptor type 1 A1166C (Table 1). Table 1 Genotype frequencies of the renin–angiotensin system variants in type 2 diabetes patients (diabetes mellitus vs non‐proliferative diabetic retinopathy vs proliferative diabetic retinopathy) The biological mechanism through which the ACE I/D polymorphism might be related to an increased risk of PDR is unclear. Serum ACE concentrations are significantly higher in those carrying the DD genotype2. Also, the final component of RAS, which is converted by ACE, has a vasoconstrictive effect, promotes the accumulation of extracellular matrix and induces plasminogen activator inhibitor‐1 production in endothelial cells3. Furthermore, DR is associated with impaired balance of retinal RAS. Increased expression of ACE/AGT overcomes this imbalance and confers protection against DR4. The present results suggest RAS polymorphism as a significant risk factor for DR in Asian Indians.

Association between RAS gene polymorphisms (ACE I/D, AGT M235T) and Henoch-Schönlein purpura in a Turkish population.

Henoch-Schönlein purpura (HSP) is a small-vessel vasculitis of autoimmune hypersensitivity, and renin-angiotensin system (RAS) regulates vascular homeostasis and inflammation with activation of cytokine release. Thus, we aimed to investigate the association between HSP and ACE I/D and AGT M235T polymorphisms. Genotyping was determined by allele specific PCR and PCR-RFLP. We obtained a significant difference in genotype distribution (p = 0.003) and allele frequencies (p < 0.001) of ACE I/D polymorphism between patients and controls, while no significant association was detected in genotype distribution (p > 0.05) and allele frequencies (p > 0.05) of the AGT M235T polymorphism. Risk assessment showed significant risk for HSP in the subjects both with the ID + DD genotype (p = 0.019, OR: 2.288, 95% CI: 1.136–4.609) and D allele (OR: D vs. I: 2.0528, 95% CI: 1.3632–3.0912, p = 0.001) while no significant risk was obtained for HSP in the subjects both with the MT + TT genotype (p = 0.312, OR: 1.3905, 95% CI: 0.7326–2.6391) and T allele (OR: T vs. M: 1.065, 95% CI: 0.729–1.557, p = 0.743). Furthermore, when patients were stratified by the presence of certain systemic complications of HSP, no significant association was detected with ACE I/D, and AGT M235T polymorphisms. Our findings suggest that ACE I/D polymorphism is significantly associated with HSP susceptibility.

Influence of Renin Angiotensin System Gene Polymorphisms on Visit-to-Visit Blood Pressure Variability in Hypertensive Patients

Visit-to-visit blood pressure (BP) variability has been reported to be a major risk for cardiovascular events. Renin angiotensin system (RAS) gene polymorphisms are reportedly genetic risk factors for cardiovascular diseases and arterial stiffness. In this study, we aimed to reveal the relationship between visit-to-visit BP variability and RAS gene polymorphisms. Study subjects included 427 essential hypertension patients from the Non-Invasive Atherosclerotic Evaluation in Hypertension study cohort, whose BP was measured during at least six outpatient visits. We analyzed the correlation between visit-to-visit variability in systolic BP (SBP) and RAS gene polymorphisms. We identified angiotensinogen M235T, angiotensin II type 1 receptor A1166C, and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms. Only ACE I/D polymorphisms were correlated with variability in diastolic BP; no gene polymorphisms were correlated with variability in SBP. RAS gene polymorphisms, especially ACE I/D polymorphisms, might genetically influence the visit-to-visit BP variability in hypertensive patients.

Association of angiotensin-converting enzyme (ACE) gene polymorphism with elevated serum ACE activity and major depression in an Iranian population

Genetic factors contribute substantially to the likelihood of developing major depressive disorder (MDD). The importance of renin–angiotensin system (RAS) elements in cognition and behaviour and their involvement in aetiology and treatment of depression imply that RAS gene polymorphism(s) associated with RAS overactivity might also be associated with depression. In the present study, genotype and allele frequencies of six common polymorphisms of genes encoding for RAS components were determined in DNAs extracted from venous blood of 191 depressed and 104 healthy individuals using polymerase chain reaction (PCR) and polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and serum angiotensin-converting enzyme (ACE) activity was assayed using a high-performance liquid chromatography (HPLC) method. The results showed, for the first time, that GG genotype of ACE A2350G was significantly associated with MDD among Iranian participants (P=0.001; odds ratio (OR)=6.2; 95% confidence interval (CI)=2.1–18.3). Significant higher serum ACE activity (P=0.0001) as well as higher diastolic blood pressure (P=0.036) were observed in depressed patients compared to the healthy control group. Depressed patients carrying GG genotype of the A2350G polymorphism had a significantly higher serum ACE activity (P=0.02) than individuals with either AA or AG genotype. In conclusion, this study supports the hypothesis of RAS overactivity in depression in that the genotype associated with higher serum ACE activity in an Iranian population was also associated with MDD.

The renin-angiotensin system gene polymorphism and the vascular disease risk in pregnant women with pre-eclampsia

In the present work the renin-angiotensin system gene polymorphisms REN (I9–83G &gt; A), AGT (M235T), AGTR1 (1166A &gt; C), AGTR2 (3123C &gt; A), BKR2 (–58T &gt; C) in pregnant women with preeclampsia, women with physiological pregnancy, healthy donors have been studied using allele-specific hybridization on the biochip. There were no statistically significant differences in genotypes distribution and allele frequencies of any genes between pre-eclampsia patients and women with normal pregnancy or donors (p &gt; 0.05). However, it was shown that C/C genotype for the AGTR2 gene is a risk factor for preeclampsia in women with chronic pyelonephritis. In addition, accuracy of predicting the risk of pre-eclampsia based on the pyelonephritis availability and genotypes for genes AGTR1, AGTR2, BKR2 was 69 % using a logistic regression method

Gene polymorphisms of angiotensin-converting enzyme and angiotensin II Type 1 receptor among chronic kidney disease patients in a Chinese population

Chronic kidney disease (CKD) is highly prevalent in Taiwan and an increasing number of patients are affected, with a high risk of progression to end-stage renal disease and huge medical expenses. It has been predicted that the presence of hypertension increases with decreasing renal function due to a decrease in sodium excretion and activation of the renin-angiotensin system (RAS). The aim of this study was to investigate the influence of genetic variants of the RAS gene on CKD. We performed a case control association study and genotyped 135 CKD patients and 270 healthy controls among Han Chinese in Taiwan. All subjects were genotyped for angiotensinogen (AGT-M235T, T174M, A-20C), angiotensin-I converting enzyme (ACE-A2350G) and angiotensin II type 1 receptor (AGTR1-A1166C, C573T, C-521T) polymorphisms of RAS genes by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Significant associations were observed in ACE-A2350G and AGTR1-C573T polymorphism between CKD patients and controls. In regard to ACE-A2350G, compared with the AA genotype the GG genotype protected against CKD (adjusted odds ratio [OR] = 0.34; p = 0.01). In regard to AGTR1-C573T, the CT genotype was a risk for CKD compared with the CC genotype (adjusted OR = 1.82; p = 0.03). We conclude that ACE-A2350G and AGTR1-C573T polymorphisms are likely candidate determinants of CKD.

Renoprotective efficacy of valsartan in chronic non‐diabetic proteinuric nephropathies with renin–angiotensin system gene polymorphisms

The renoprotective effects of angiotensin receptor blockers vary considerably among individuals. We investigated the renoprotective effects of valsartan according to polymorphisms of the renin-angiotensin system and transforming growth factor-b1 (TGFB1) genes in patients with chronic non-diabetic proteinuric nephropathies. Two hundred and thirty-nine non-diabetic patients with proteinuria of at least 1 g/day were enrolled. Patients received 80 g of valsartan daily, followed by 160 mg/day after 6 weeks. The follow-up period was 18 months. The status of the angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T, type 1 angiotensin II receptor (ATR1) A1166C, and TGFB1 C509 and T869C polymorphisms was determined in 162 patients. Valsartan treatment caused a significant reduction in proteinuria from baseline throughout the study in patients with each genotype of the ACE, AGT and TGFB1 genes. However, patients with the ATR1 AC genotype had no significant reduction in proteinuria from baseline throughout the study course. The median reductions in proteinuria after 6 months were 45.7% and 10.8% in the patients with the ATR1 AA and AC genotypes, respectively (P = 0.034). The annual change in the estimated glomerular filtration rate did not differ significantly among the genotypes for each gene. On multiple regression analysis, the change in proteinuria after 6 months of treatment was independently associated with the ATR1 genotype and the change in blood pressure (P = 0.005 and 0.019, respectively). Valsartan treatment significantly reduced the blood pressure and urinary protein excretion of patients with chronic non-diabetic proteinuric nephropathies. Interindividual differences in the anti-proteinuric effect of valsartan may be related partly to the ATR1 A1166C polymorphism.

Influence of Renin-Angiotensin System Gene Polymorphisms on the Risk of ST-Segment-Elevation Myocardial Infarction and Association with Coronary Artery Disease Risk Factors

Recent advances in molecular biology have made it possible to identify numerous polymorphisms of the renin-angiotensin system, which play an important role in the etiology of cardiovascular disease. The aims of the study were (i) to assess the distribution of the angiotensin II type 1 receptor (AGTR1) gene 1166A/C polymorphism and two polymorphisms of the angiotensinogen (AGT) gene (Met235Thr and Thr174Met) in patients with ST-segment-elevation myocardial infarction (STEMI) who underwent coronary angiography, compared with healthy volunteers; (ii) to determine if there was any correlation between these polymorphisms and risk of STEMI; and (iii) to assess the association of the examined polymorphisms with such classic cardiovascular risk factors as hypertension, diabetes mellitus, obesity (based on a body mass index ≥25 kg/m2), smoking, dyslipidemia, and family history of cardiovascular disease. A total of 100 patients (mean age 57 ± 10 years [range 31-76 years]; 21% women) with diagnosed STEMI and a control group consisting of 95 healthy volunteers (mean age 38 ± 11 years [range 17-60 years]; 20% women) were investigated for the AGTR1 1166A/C polymorphism and two variants of AGT (Met235Thr and Thr174Met). All patients received standard therapy for STEMI. There were significant differences in the distribution of genotypes and the AGT Met174 allele for AGT Thr174Met polymorphism between patients and healthy subjects (p < 0.05). The AGTR1 1166A/C polymorphism genotype frequencies were significantly different in patients with hypertension compared with normotensive individuals. Specifically, the AGTR1 1166 AA genotype was twice as common in patients with hypertension as in those without (67% vs 33%), while the AC and CC genotypes were found predominantly in normotensive patients (p = 0.0016). The variant 1166C allele was much more common in patients without hypertension (67%) than in patients with hypertension (33%; p = 0.0006). The variant AGT Thr235 allele was more common in patients without a family history of cardiovascular disease than in patients with this risk factor (p < 0.05). The odds ratio (OR) for STEMI in patients with the heterozygous AGT 174 Thr/Met genotype was increased to 1.884 (95% confidence interval [CI] 1.03, 3.446; p < 0.05), while the OR calculated for carriers of the AGT Met174 allele was 2.038 (95% CI 1.129, 3.68; p = 0.0182). Significant genotypic associations of combinations of renin-angiotensin system gene polymorphisms in STEMI were not observed. The most powerful predictive value for STEMI was represented by the Thr/Met genotype and the Met174 allele of the AGT Thr174Met gene polymorphism. In our study, in contrast to observations reported by other authors, the AA genotype of the AGTR1 1166A/C gene polymorphism - much more than other genotypes - was associated with hypertension.

The association of hypertension with renin–angiotensin system gene polymorphisms in the Lebanese population

The study objective was to examine the association of hypertension in the Lebanese population with three renin-angiotensin system gene polymorphisms (RAS): angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin-receptor type 1 (AT1R). A total of 270 subjects (124 hypertensive vs 146 normotensive) were genotyped for ACE insertion (I)/deletion (D), AGT (M235T), and AT(1)R (A1166C) gene polymorphisms by polymerase chain reaction and restriction fragment length polymorphism. The studied genes showed no deviation from Hardy-Weinberg equilibrium. No association could be reported with the ACE I/D polymorphism, although the D allele frequency was high (77%) in patients. AGT TT genotype prevalence was found to be lower in hypertensive versus normotensive subjects (p<0.0001). AT(1)R CC and AC genotypes were significantly more frequent in hypertensive than normotensive subjects (p<0.0001). The first conducted study on the RAS gene polymorphisms in Lebanese hypertensive patients demonstrated a possible association of the AGT T and AT(1)R C alleles with hypertension.

Interactions of Renin–angiotensin System Gene Polymorphisms and Antihypertensive Effect of Benazepril in Chinese Population

Angiotensin-converting enzyme inhibitors are widely used antihypertensive drugs with individual response variation. We studied whether interactions of AGT, AGTR1 and ACE2 gene polymorphisms affect this response. Our study is based on a 3-year field trial with 1831 hypertensive patients prescribed benazepril. Generalized multifactor dimensionality reduction was used to explore interaction models and logistic regressions were used to confirm them. A two-locus model involving the AGT and ACE2 genes was found in males, the sensitive genotypes showed an odds ratio (OR) of 1.9 (95% CI: 1.3-2.8) when compared with nonsensitive genotypes. Two AGT-AGTR1 models were found in females, with an OR of 3.5 (95% CI: 2.0-5.9) and 3.1 (95% CI: 1.8-5.3). Gender-specific gene-gene interactions of the AGT, AGTR1 and ACE2 genes were associated with individual variation of response to benazepril. Further studies are needed to confirm this finding.

Polymorphisms of renin-angiotensin system genes as a risk factor for high-altitude pulmonary oedema

The genes of the renin--angiotensin system (RAS) play an important role in the regulation of pulmonary vascular tone. Although studies on individual genes polymorphisms have reported association with high-altitude pulmonary oedema (HAPE), studies on multiple genes or epistasis are lacking. We therefore investigated the association of the RAS polymorphisms with HAPE. In a case-control design, we screened 163 HAPE-resistant/controls (HAPE-r) and 160 HAPEpatients (HAPE-p) of Indian origin for eight polymorphisms of four RAS genes, ACE, AGT, AGTR1 and AGTR2. Significant difference in genotype and allele frequencies of the ACE I/D and AGT M235T polymorphisms was observed between HAPE-p and HAPE-r (p < 0.05). In three-locus haplotype analysis of AGT the haplotype GTM was significantly higher in HAPE-p (29%) and haplotype GTT in HAPE-r (27%) after Bonferroni correction (p < 0.006). The differences were insignificant for polymorphisms from AGTR1 and AGTR2. The MDR (multifactor dimensional reduction) approach for gene--gene interaction depicted individual polymorphism M235T as the best disease predicting model (cross validation consistency, CVC = 10/10). We found a significant association of D allele of ACE and M allele of AGT with HAPE. The findings are supported at the haplotypic level as well as through nested genetic interaction between the RAS gene polymorphisms using the MDR approach.

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.

T14.3 Late obstetric complications in antiphospholipid syndrome: clinical presentation and management

Renin-angiotensin System is essential for the homeostasis of blood pressure in humans. The roles of renin-angiotensin system gene polymorphisms including angiotensinogen, angiotensin-converting enzyme, renin and angiotensin II receptor, type 1 genes in the pathogenesis of preeclampsia have been extensively studied, but most association studies produced either negative or inconsistent results. Prolylcarboxypeptidase encodes a lysosomal enzyme and is a regulator for both renin-angiotensin system and the kallikrein-kinin system. There is no published study on prolylcarboxypeptidase gene and preeclampsia.We investigated the independent and joint association of five polymorphisms in angiotensinogen, angiotensin-converting enzyme, and prolylcarboxypeptidase gene and chronic hypertension with the risk of preeclampsia in 125 preeclamptic and 1040 non-preeclamptic black women enrolled at the Boston Medical Center. We used logistic regression models to estimate the odds ratios of risk for preeclampsia associated with each gene polymorphism and its joint association with chronic hypertension.No association was found in four polymorphisms in angiotensinogen and angiotensin-converting enzyme. Prolylcarboxypeptidase E112D (rs2298668) D allele along and jointly with chronic hypertension were associated with a significantly increased risk of preeclampsia. Compared to women with homozygous EE genotype and without chronic hypertension, higher risks of preeclampsia were observed in DD women without chronic hypertension (OR = 3.7, 95% CI, 1.2 - 12.4) and EE women with chronic hypertension (OR = 9.1, 95% CI: 4.7 - 17.6). Women with both D allele and chronic hypertension had the highest risk (OR = 158, 95% CI, 25-infinite). This finding was validated in an independent sample of 1,015 non-black women. We further compared the prolylcarboxypeptidase transcript levels in peripheral blood cells of 23 preeclamptic (30% with chronic hypertension) and 51 non-preeclamptic (6% with chronic hypertension) women 2 - 3 days after delivery. The PRCP transcript levels were lower in ED/DD women than in EE woman (P = .03) and lower in preeclamptic women than in non-preeclamptic women (P = .007).Our data showed that prolylcarboxypeptidase D allele coupled with chronic hypertension was associated with a significantly increased risk of preeclampsia in both black and non-black women. Gene expression assays lent further support for the functional significance of prolylcarboxypeptidase in the etiology of preeclampsia.

Renin-Angiotensin System Associated with Risk of Upper GI Mucosal Injury Induced by Low Dose Aspirin

We have previously shown that co-treatment of angiotensin type 1 receptor (AT1R) blocker (ARB) or angiotensin converting enzyme (ACE) inhibitor seem to reduce peptic ulcer among patients taking low dose aspirin. It is reported that a series of renin-angiotensin system (RAS) gene polymorphisms significantly influence the rate of the gene transcription. The aim of this study was to examine the genotypes of RAS genes related to the risk of peptic ulcer and ulcer bleeding among patients taking low dose aspirin. Patients taking 100mg of aspirin who were planning to undergo endoscopy for surveillance or who had history of recent upper GI ulcer bleeding were included. ACE (Ins/Del), angiotensinogen (AGT; G-217A, A-20C, A-6G, T174M, M235T), and AT1R (T-713G, C-521T, A1166C) genotypes were determined by PCR or PCR-RFLP. Four hundred twenty-five patients were enrolled including 68 patients with peptic ulcer and 20 patients with ulcer bleeding. Co-treatment of ARB was significantly associated with peptic ulcer and ulcer bleeding. AGT-20 CC (adjusted OR 4.94, 95% CI 1.21-20.2) was significantly associated with ulcer bleeding. The CC genotype of AT1R-521 was significantly associated with peptic ulcer only in the subgroup taking neither ACE inhibitor nor ARB. Co-treatment of ARB reduces peptic ulcer and bleeding among patients taking low dose aspirin. RAS may play an important role in the development of upper GI mucosal injury induced by low dose aspirin.

Renin-angiotensin system gene polymorphisms in children with Henoch—Schönlein purpura in West China

It has been suggested that renin-angiotensin system (RAS) gene polymorphism is involved in the pathogenesis of Henoch-Schönlein purpura (HSP) with conflicting reports. We therefore investigate the effect of RAS gene polymorphism on HSP susceptibility and severity in a Chinese cohort. The study included 142 children with HSP and 218 healthy controls that were genotyped for RAS gene polymorphisms. Significantly, differences of T174M-T and ACE-D frequency were found between HSP patients and controls (p(alleo) = .002, OR(alleo) = 2.001; p(alleo) = .007, OR(alleo) = 1.533, respectively). We also found correlations between ACE-I/D and Agt T174M with multiple organ involvements, with significant differences in ACE-D in renal groups (p < 0.05) and Agt T174M in non-renal (p(joint) = .002, p(GI) = .042). Furthermore, decreasing M235T-T and increasing ACE-D were found associated with serious renal complications (p = .019, p = .016). Additionally, ACE-I/D and T174M were significantly associated with high clinical score patients, as opposed to low clinical score patients, when patients were scored depending on the severity of overall complications (p = .045, p = .026). We suggest that RAS gene polymorphisms (ACE-I/D, M235T or T174M) are significantly associated with susceptibility to HSP, organ involvement, and disease severity, which largely account for individual prognosis.

Association of angiotensin converting enzyme and angiotensin type 2 receptor gene polymorphisms with renal damage in posterior urethral valves

To examine the association with renal damage in patients with posterior urethral valves (PUV) of two renin-angiotensin system gene polymorphisms: angiotensin converting enzyme insertion/deletion (ACE I/D) and angiotensin type 2 receptor (AT2R A1332G), PATIENTS AND METHODS: In 120 patients with PUV, after stabilization, transurethral fulguration or a Blocksom vesicostomy was performed. Records were reviewed for age at diagnosis, biochemical renal function at diagnosis, results of urine cultures, voiding cystourethrograms, radiologic, sonographic and nuclear medicine scan findings, and follow-up data. ACE I/D genotypes were determined by the polymerase chain reaction using allele specific primers. The frequency of the ACE DD genotype was significantly higher in patients with chronic kidney disease (P=0.02) and renal scarring (P=0.05). These genotypes were also associated with a statistically higher incidence of vesicoureteral reflux, diurnal incontinence, proteinuria and hypertension. A significantly higher frequency of the AT2R GG genotype was found in PUV patients as compared to healthy unrelated control subjects (P=0.001), and in PUV patients with scarring (P=0.02). The ACE DD and AT2R GG genotypes are associated with chronic kidney disease and scarring in PUV patients. The GG genotype incidence is higher among PUV patients compared to the control population, and further studies in this area may help understanding of the genetic basis of PUV.

Analysis of polymorphism in Renin Angiotensin System and other related genes in South Indian chronic kidney disease patients

Background Several Renin Angiotensin System (RAS) polymorphisms alter the homeostasis to an abnormal state. Similarly, other genes such as Nephrin (NPHS1) and Podocin (NPHS2) contribute to the loss of renal function during renal diseases. In Indian population, studies in RAS and other renal specific gene polymorphisms in Chronic Kidney Disease (CKD) patients are scanty. Methods We examined 118 CKD patients and 98 control subjects for the occurrence of common polymorphisms in angiotensin converting enzyme insertion/deletion ( ACE; I/D), angiotensinogen ( AGT; M235T), chymase ( CMA; − 1903G > A), angiotensin receptor type-1 ( AGTR1-1166A > C), methylene tetrahydrofolate reductase ( MTHFR; 677C > T), nephrin ( NPHS1; R1160X) and podocin ( NPHS2; R291W and R229Q). Result Significant association was observed in AGT-M235T polymorphism between CKD patients and controls. The frequency of TT genotype was higher in CKD patients when compared with controls (0.39 vs. 0.14; χ 2 = 20.3, P < 0.001). ACE- DD genotype showed a higher level of systolic pressure with a median of 166 mmHg ( P < 0.05) when compared to II and ID genotypes. Two heterozygous conditions of NPHS2-R229Q polymorphism were found among 105 CKD patients. No significant associations were found in genotype frequencies in other above polymorphisms between CKD patients and controls. Conclusion Asian Indian population with AGT-TT genotypes may have a higher relative risk towards CKD with odds ratio (OR) 3.98 (95% CI = 1.92–8.25; P = 0.0002).