Angiotensin II Type 1 Receptor Polymorphisms Research Articles

In silico prediction of ARB resistance: A first step in creating personalized ARB therapy.

Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are among the most prescribed drugs. However, ARB effectiveness varies widely, which may be due to non-synonymous single nucleotide polymorphisms (nsSNPs) within the AT1R gene. The AT1R coding sequence contains over 100 nsSNPs; therefore, this study embarked on determining which nsSNPs may abrogate the binding of selective ARBs. The crystal structure of olmesartan-bound human AT1R (PDB:4ZUD) served as a template to create an inactive apo-AT1R via molecular dynamics simulation (n = 3). All simulations resulted in a water accessible ligand-binding pocket that lacked sodium ions. The model remained inactive displaying little movement in the receptor core; however, helix 8 showed considerable flexibility. A single frame representing the average stable AT1R was used as a template to dock Olmesartan via AutoDock 4.2, MOE, and AutoDock Vina to obtain predicted binding poses and mean Boltzmann weighted average affinity. The docking results did not match the known pose and affinity of Olmesartan. Thus, an optimization protocol was initiated using AutoDock 4.2 that provided more accurate poses and affinity for Olmesartan (n = 6). Atomic models of 103 of the known human AT1R polymorphisms were constructed using the molecular dynamics equilibrated apo-AT1R. Each of the eight ARBs was then docked, using ARB-optimized parameters, to each polymorphic AT1R (n = 6). Although each nsSNP has a negligible effect on the global AT1R structure, most nsSNPs drastically alter a sub-set of ARBs affinity to the AT1R. Alterations within N298 -L314 strongly effected predicted ARB affinity, which aligns with early mutagenesis studies. The current study demonstrates the potential of utilizing in silico approaches towards personalized ARB therapy. The results presented here will guide further biochemical studies and refinement of the model to increase the accuracy of the prediction of ARB resistance in order to increase overall ARB effectiveness.

In silico Approach for Exploring the Role of AT1R Polymorphism on its Function, Structure and Drug Interactions.

AT1R (Angiotensin II type 1 receptor) is the main component of RAS (renin-angiotensin system) system, which activates when ANG II (angiotensin II) binds to it. AT1R helps in maintaining osmotic homeostasis and blood pressure regulation. A huge number of polymorphism are associated with AT1R and few of them were studied and found to be associated with the diseases and drug efficacy. Although it is a very important receptor most of the polymorphisms (SNPs) were not studied for their implications in diseases. A huge number of polymorphisms are reported in the databases for AT1R, which provide an avenue to explore these polymorphisms for their implications in protein structure, function and drug efficacy. In the current study, all the SNPs (10234) reported in NCBI were analyzed and SNPs that were important in protein structure and drug interactions were identified. Structures of these polymorphic forms were modeled and in silico drug interaction studies were carried out. The result of the interaction studies with polymorphism was in correlation with the reported case. Two SNP mutated structures of AT1R i.e. rs780860717 (G288T), rs868647200 (A182C) show considerably less binding affinities in the case of all angiotensin receptor blockers (ARBs). As a result, these polymorphisms may show less efficacy toward these ARBs. The other mutated structures rs12721226 (A163G), rs749234826 (A292G), rs775810028 (A87G), show increased binding affinities in case of Eprosartan and most of the mutated structures shows increased binding affinity toward Telmisartan than the wild type AT1R. Similarly, these polymorphisms may show increased efficacy in the case of these two ARBs. The outcome of the study will help in designing better drugs in the near future with broader spectrum. Furthermore, in vitro and in vivo studies can be designed according to the current results.

Associations Between Polymorphisms of Endothelial Nitric Oxide Synthase, Matrix Metalloproteinase 3, Angiotensinogen, and Angiotensin II Type 1 Receptor and Risk of Restenosis After Percutaneous Coronary Intervention: A Meta-analysis

PurposePrevious studies have reported controversial results regarding the risk of restenosis with polymorphisms of endothelial nitric oxide synthase (eNOS), matrix metalloproteinase 3 (MMP-3), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1R) after percutaneous coronary intervention (PCI). This study aimed to summarize the association between these polymorphisms and risk of restenosis after PCI. MethodsWe searched the electronic databases of PubMed, Embase, Cochrane's Library, and ClinicalTrials.gov for studies on the association of eNOS, MMP-3, AGT, and AT1R polymorphisms with restenosis. FindingsA total of 17 studies (7781 patients) were analyzed, including 5 studies on eNOS G298A (n = 912), 5 studies on MMP3 5A/6A (n = 4519), 6 studies on AGT M235T (n = 1801), and 7 studies on AT1R A1166C (n = 2477). For the G298A variant of the eNOS gene, the allele odds ratio (OR) was 1.685 (95% CI, 1.269–2.338; P < 0.001), the heterozygote OR was 2.144 (95% CI, 1.490–3.085; P < 0.001), the dominant OR was 2.078 (95% CI, 1.462–2.954; P < 0.001), and the overdominant OR was 0.496 (95% CI, 0.348–0.706; P < 0.001). For the 5A/6A variant of the MMP3 gene, the heterozygote OR was 0.839 (95% CI, 0.722–0.975; P = 0.022), the dominant OR was 0.846 (95% CI, 0.733–0.976; P = 0.022), and the overdominant OR was 1.141 (95% CI, 1.001–1.301; P = 0.049). For the M235T variant of the AGT gene, the heterozygote OR was 1.594 (95% CI, 1.179–2.155; P = 0.002), the dominant OR was 1.437 (95% CI, 1.077–1.918; P = 0.014), and the overdominant OR was 0.694 (95% CI, 0.555–0.869; P = 0.001). Positive results were observed in the AT1R gene A1166C polymorphism under 3 models (homozygote OR = 2.009; 95% CI, 1.433–2.816; P < 0.001; recessive OR 1.874; 95% CI, 1.353–2.595; P < 0.001; and dominant OR = 1.350; 95% CI, 1.105–1.649; P = 0.003). ImplicationsThe G298A variant of eNOS, the 5A/6A variant of MMP3, the M235T variant of AGT, and the A1166C variant of A1TR may increase the risk of restenosis after PCI.

Risk and severity of psoriasis vulgaris in relation to angiotensin II type 1 receptor gene polymorphism and metabolic syndrome.

BackgroundPsoriasis vulgaris is a chronic inflammatory and proliferative skin disease, characterized by the formation of itchy, erythematous skin patches or plaques. Patients with psoriasis are at an increased risk of developing metabolic syndrome, including obesity, hypertension, diabetes, and atherosclerosis. Recently, angiotensin II (Ang II) has been reported to be associated with the development of psoriasis. Ang II not only increases the blood pressure but is also a potent proinflammatory modulator and functions through interaction with angiotensin II type 1 receptor (AT1R). Moreover, it is hypothesized that the AT1R gene expression could be correlated with the severity of psoriasis and/or metabolic syndrome.AimWe examined the association of Ang II type 1 receptor (AT1R) A1166C gene polymorphisms and metabolic syndrome with the severity of psoriasis.Patients and methodsThe present case-control study included 25 patients with psoriasis vulgaris and 25 healthy subjects in Egypt. The psoriasis lesions in the patient group were assessed using the psoriasis area and severity index (PASI) score. The AT1R polymorphism A1166C (rs5186) was studied using restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) amplification of the gene from the whole blood sample in both groups. Serum lipid profile and blood sugar levels were assessed post 12 h and 8 h fasting, respectively, in both groups. The severity of metabolic syndrome was evaluated using the severity score.ResultsThe results of the present study demonstrated that the AT1R A1166C gene polymorphisms increased the risk of developing psoriasis in the Egyptian population. We found that 70% of patients with AC genotype and 100% of patients CC genotype reported a PASI score >20 and were considered to be severe cases with a statistically significant difference as compared with patients with AA genotype (p=0.003). In addition, a high statistically significant difference (p=0.001) existed among AT1R genotypes with respect to the percentage of metabolic syndrome in psoriasis patients. Similarly, a statistically significant difference (p=0.004) among AT1R genotypes with respect to metabolic score was found, with the highest level of score and percentage observed in patients with CC genotype than in patients with AC genotype. The lowest level was present among those with AA genotype.ConclusionPatients with psoriasis expressing the C allele of AT1R1166 are susceptible to developing metabolic syndrome and have higher PASI scores as compared with patients carrying the A allele.

A1166C polymorphism of the angiotensin II type 1 receptor gene contributes to hypertension susceptibility: evidence from a meta-analysis

Background The angiotensin II type 1 receptor (AT1R) gene is a prime candidate for polymorphisms that could contribute to hypertension. A polymorphism in the 3’ untranslated region, leading to the transversion of adenine to cytosine at position 1166, has been the most-studied variant. However, the results have been inconsistent, and we therefore performed a meta-analysis to evaluate the association of this polymorphism with hypertension.Methods We conducted an extended a computer-based literature search of PubMed and Web of Knowledge up to November 30, 2015. The extracted data were analysed statistically, and pooled odds ratios with 95% confidence intervals were calculated to assess the strengths of associations using Review Manager software (version 5.2).Results After removing 5 studies that were not consistent with the Hardy-Weinberg equilibrium, we finally collected 41 case–control studies involving 11,837 cases and 11,020 controls to evaluate the association between AT1R polymorphisms and hypertension. We found that the risk of hypertension was higher for allele C than for allele A under the codominant model, significantly higher for genotype CC + AC than for genotype AA under the dominant model, and significantly higher for genotype CC + AC in Caucasians.Conclusion This meta-analysis suggests that the AT1R 1166 CC + AC genotype consistently confers susceptibility to hypertension and that early preventive measures should be applied in clinical settings according to patient genotypes.

Susceptibility and progression of end stage renal disease are not associated with angiotensin II type 1 receptor gene polymorphism

Context: The role of the angiotensin II type 1 receptor (AT1R) gene polymorphism, A1166C, has been shown to be associated with end stage renal disease (ESRD) and its progression. There is also some evidence that HLA class II alleles are associated with ESRD independent of other factors. Objective: To examine the association between AT1R gene polymorphism in the susceptibility and progression to ESRD in patients with chronic renal failure and to investigate if the AT1R genotypes and HLA-DR alleles predict the time to ESRD. Materials and methods: Genotyping was performed in 50 ESRD patients and 44 control subjects for the AT1R A1166C gene polymorphism using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). ESRD patients were examined for HLA-DRB1 alleles according to a reverse hybridization line probe assay. Results: Allele and genotype frequencies of the AT1R polymorphism did not differ significantly between ESRD patients and controls. Furthermore, there was no association between the AT1R gene polymorphism or HLA-DRB1 alleles with the time to the occurrence of end stage failure. Discussion and Conclusion: We concluded that the AT1R genotype does not contribute to the genetic susceptibility of ESRD and is not associated with progression of chronic kidney failure to ESRD.

XRCC1 399Arg-related genotype and allele, but not XRCC1 His107Arg, XRCC1 Trp194Arg, KCNQ2, AT1R, and hOGG1 polymorphisms, are associated with higher susceptibility of endometriosis

X-ray repair cross-complementing group 1 (XRCC1) and human 8-oxoguanine glycosylase 1 (hOGG1) play important roles in base excision repair. KCNQ genes comprising voltage-gated ion-channels related with cell stability. Angiotensin II type 1 receptor (AT1R) is related with angiogenesis, which influence endometriosis growth, invasion and regression. We aimed to investigate whether these polymorphisms were associated with endometriosis susceptibility. Women were divided []: endometriosis (n = 136 []); non-endometriosis groups (n = 112). XRCC1 (codon 107, 194, 399), hOGG1, KCNQ2, AT1R polymorphisms were amplified by PCR and detected by electrophoresis after restriction enzyme (RsaI, HpaII, MspI, Fnu4HI, Ava II, Dde I) digestions. Genotypes and allelic frequencies in both groups were compared. Proportions of XRCC1 Arg399Gln*GG/GA/AA and G/A allele between both groups were []: 41.9/53.7/4.4% and 68.8/31.2% []; 30.4/54.5/15.1% and 57.6/42.4% (p < 0.05). Other 5 polymorphisms (XRCC1 codon 107 and 194, hOGG1, KCNQ2, and AT1R) between both groups were non-significantly different. Proportions of XRCC1 107*AA/AG/GG and XRCC1 194*TT/TC/CC between both groups were []: 3.7/27.2/69.1% and 5.8/34.6/59.6% []; 2.6/21.4/75.8% and 11.6/37.5/50.9%. HOGG1*CC/CG/GG, KCNQ2*AA/AC/CCC and AT1R*AA/AC/CC were []: 14.8/42.6/42.6, 14/41.9/44.1 and 92.6/7.4/0% []; 11.6/50/38.4, 17/50/33 and 100/0/0%. We concluded that XRCC1 399 Arg-related genotype and allele are correlated with higher susceptibility to endometriosis, which suggested its association with endometriosis pathogenesis. XRCC1 107 and 194, hOGG1, KCNQ2, and AT1R are not associated with endometriosis susceptibility.

Haplotype-based association of ACE I/D, AT1R 1166A>C, and AGT M235T polymorphisms in renin–angiotensin–aldosterone system genes in Korean women with idiopathic recurrent spontaneous abortions

Objectives The objective of this study was to determine whether or not the angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensin II type 1 receptor (AT1R), and angiotensinogen (AGT) gene polymorphisms are associated with idiopathic recurrent spontaneous abortions (RSAs) in Korean women. Study design A total of 251 patients with unexplained consecutive pregnancy losses, and 126 healthy controls with at least one live birth and no history of pregnancy loss. Result The odds ratios (ORs) of the ACE ID (OR = 2.423; 95% confidence interval (CI) = 1.417–4.142; p = 0.001) and the ACE II (OR = 2.050; 95% CI = 1.143–3.675; p = 0.018) for the ACE DD genotype were significantly different between patients with idiopathic RSA and controls; however, there were no significant differences between patients and controls with respect to the AT1R 1166A>C and AGT M235 T polymorphisms. In a haplotype-based analysis of I-A ( p = 0.010), D-A ( p = 0.004), I-A-T ( p = 0.033), D-A-T ( p = 0.0005), and D-C-T ( p = 0.013) polymorphism pairs with synergistic effects derived by the MDR method in patients and in controls showed significant results. Conclusion This study suggests that ACE, AT1R and AGT polymorphisms and haplotypes are a genetic determinant for the risk of idiopathic RSA in Korean women.

Association of angiotensin I converting enzyme (insertion/deletion) and angiotensin II type 1 receptor (A1166C) polymorphisms with breast cancer prognostic factors in iranian population

It has been indicated that renin-angiotensin system (RAS) has role in various steps of cancer progression. The presence of RAS components has been shown in normal and breast cancer tissue. insertion/deletion (I/D) is one of angiotensin I converting enzyme (ACE) polymorphisms and A1166C is one of angiotensin II type-1 receptor (AT1R) polymorphisms which have been associated with various diseases such as cardiovascular diseases. In the present study, we aimed to substantiate the putative significance of ACE and AT1R on breast cancer biology by investigating the influence of their gene polymorphisms on breast cancer progression. The I/D and A1166C polymorphisms were evaluated by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), respectively in 70 breast cancer patients diagnosed with invasive breast cancer and 70 healthy women. Breast cancer prognostic factors were obtained from medical and pathology reports of patients. There was no significant difference between cases and controls for ACE (I/D) (P = 0.15) and AT1R (A1166C) genotypes (P = 0.86). In breast cancer patients, when DD genotype was used as reference group, the combination of II and ID genotypes was associated with increased HER-2 expression (P = 0.020; OR, 4.58; 95% CI, 1.26-16.60). Also, when AA genotype was used as reference group, the AC genotype was associated with higher tumor TNM stage (P = 0.024; OR, 4.66; 95% CI, 1.18-18.35). This is the first study indicating that ACE (I/D) polymorphism is associated with HER-2 expression and AT1R (A1166C) polymorphism is associated with tumor TNM stage in breast cancer patients.

Angiotensin II type 1 receptor gene polymorphism could influence renoprotective response to losartan treatment in type 1 diabetic patients with high urinary albumin excretion rate

Diabetic nephropathy (DN) is a clinical syndrome characterized by persistent albuminuria, increasing arterial blood pressure and progressive decline in glomerular filtration rate (GFR). When persistent albuminuria is established, antihypertensive treatment becomes most important factor in slowing the progression of diabetic glomerulopathy. The aim of this study was to examine if renoprotective response to a short-term losartan therapy depends on 1166 A/C gene polymorphism for its target receptor. The study included 35 patients with diabetes mellitus type 1 and persistently high urinary albumin excretion rate (UAE: > 30 mg/24 h), genotyped for the 1166 A/C gene polymorphism for the angiotensin II type 1 receptor (AT1R). The participants were segregated into 3 genotype groups according to combinations of A or C allele: AA (16%), AC (15%) and CC (11%). The patients received losartan 50 mg daily for 4 weeks, following 100 mg daily for another 8 weeks. At baseline and after 12 weeks of the treatment period UAE, blood pressure, GFR and filtration fraction (FF) were determined. After 12 weeks of the treatment with losartan, albuminuria was reduced from baseline by 9% [95% confidence interval (CI): 1-17, p = 0.039] in the AA genotype, and by 11% (95% CI: 6-17, p = 0.0001) in the AC genotype. Losartan treatment reduced albuminuria in the CC group by 5% (95% CI: -13-22, p = 0.47). Glomerular filtration rate remained unchanged in all genotype groups. Filtration fraction was significantly reduced from baseline by 0.018 +/- 0.024 (p = 0.012) only in the AC genotype. In the AA genotype, FF was reduced from baseline by 0.017 +/- 0.03 (p = 0.052), and in the CC genotype by 0.01 +/- 0.008 (p = 0.092). In the AA group, systolic blood pressure declined from 136 +/- 24 mmHg at baseline, to an average of 121 +/- 18 mmHg at the end of the study (p = 0.001). The AC group achived reduction from 131 +/- 10 mmHg at baseline to 115 +/- 7 mmHg (p = 0.001) during the investigation period. In the AA genotype group losartan reduced diastolic blood pressure from 86 +/- 13 mmHg at baseline to 78 +/- 8 mmHg (p = 0.004), and in the AC genotype from 88 +/- 5 mmHg at baseline to 11.7 +/- 5.6 mmHg during the investigation period (p = 0.001). In the CC genotype diastolic blood pressure reduction remained nonsignificant (p = 0.066). The results of our small sample size study provide the evidence that 1166 A/C AT1R polymorphism could be associated with the renoprotective response to losartan therapy.

Angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1R) gene polymorphisms in generalized aggressive periodontitis

Aim Host response to periodontopathic microorganisms can be modulated by genetic factors. Accumulated evidence highlighted the role of renin–angiotensin system (RAS) in inflammatory response thus potential implication of this molecular system in the pathogenesis of periodontitis can be suggested. The present study investigated common genetic variants of molecules within the RAS family namely angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1R) in relation to generalized aggressive periodontitis (G-AgP). Methods DNA was obtained from peripheral blood of 103 G-AgP patients and 100 periodontally healthy subjects. ACE I/D, AGT M235T and AT1R A1166C polymorphisms were genotyped by polymerase chain reaction and restriction fragment length polymorphism method. Chi-square, ANOVA and logistic regression were used in statistical analyses. Results Both ACE I/D and AT1R polymorphisms were similar in G-AgP and healthy groups ( p > 0.05). G-AgP subjects exhibited decreased AGT TT genotype and T allele frequency as compared to healthy subjects ( p < 0.05). The same trend was also observed in the nonsmoker subgroup regarding investigated RAS polymorphisms. Conclusions Present findings suggest that AGT M235T TT genotype and T allele might be associated with decreased risk for G-AgP in Turkish population.

The Relationship Between the Plasma Concentration of Irbesartan and the Antihypertensive Response Is Disclosed by an Angiotensin II Type 1 Receptor Polymorphism: Results From the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) Trial

The aim of this study was to investigate the effect of the plasma concentration of irbesartan, a specific angiotensin II type 1 receptor (AT1R) antagonist, and the blood pressure response in relation to AT1R gene polymorphisms. Plasma irbesartan was analyzed in 42 patients with mild-to-moderate hypertension and left ventricular hypertrophy from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) trial, who were treated with irbesartan as monotherapy for 12 weeks. Blood pressure and irbesartan concentration were measured at trough, i.e., 24 +/- 3 h after the last dose. Five AT1R gene polymorphisms were analyzed by minisequencing. Neither the plasma concentration of irbesartan, nor any of the AT1R polymorphisms were associated with the blood pressure response to irbesartan treatment. However, the interaction term between the plasma concentration of irbesartan and the AT1R C5245T polymorphism was related to the reduction in systolic blood pressure after 12 weeks of treatment (P = 0.025). Furthermore, the plasma concentration of irbesartan was related to the change in systolic blood pressure in individuals homozygous for the AT1R 5245 T allele (r = -0.56, P = 0.030), but not for other genotypes. There was an association between plasma concentrations of irbesartan and the blood pressure response for hypertensive patients with AT1R 5245 TT. Because of the small sample size, this study needs to be viewed as hypothesis generating. This is the first study, to our knowledge, indicating that the concentration-response relationship of an antihypertensive drug may be genotype dependent.

AGT and ACE genes influence classic mitral valve prolapse predisposition in Marfan patients

Background In Marfan syndrome, the mitral valve prolapse, ranging from nonclassic to classic form on the basis of the leaflet thickness, is a common condition characterized by a highly variable structural abnormality. We investigated the role of angiotensinogen ( AGT) M235T, angiotensin converting enzyme ( ACE) I/D and angiotensin II type 1 receptor ( AT1R) A1166C polymorphisms in influencing the susceptibility to classic or non-classic mitral valve prolapse in Marfan patients. Methods We studied 135 Marfan patients with mitral valve prolapse, diagnosed by echocardiography. AGT, ACE, and AT1R polymorphisms were identified by polymerase chain reaction-based restriction analysis. Results The frequency of the ACE D, but not AGT 235T and AT1R 1166C allele, was significantly higher in patients with classic mitral valve prolapse in comparison to that observed in the non-classic one ( p = 0.03). The percentage of subjects with the contemporaneous presence of ACE D and AGT 235T alleles was significantly higher in the classic mitral valve prolapse group in comparison to the non-classic one (79% vs. 55%, respectively; p = 0.008). The concomitant presence of these two alleles was associated with increased susceptibility to the classic mitral valve prolapse ( OR 3.02, p = 0.016). Conclusions Our findings show a possible role of ACE and AGT genes as predisposing factors to classic mitral valve prolapse in Marfan patients, thus suggesting a role of renin angiotensin system genes in modulating mitral valve abnormality, and the need for an interventional study with angiotensin II type 1 receptor antagonists, which considers the leaflet thickness progression in Marfan patients with MVP.

Genetic polymorphisms of the renin-angiotensin system in end-stage renal disease

End-stage renal disease (ESRD) is a complex phenotype resulting from underlying kidney diseases of different etiologies as well as from environmental and genetic factors. The responsible genes influencing the development and rate of progression to ESRD have yet to be defined. We examined an association of the three renin-angiotensin system (RAS) gene polymorphisms with renal disease and progression to ESRD in dialyzed patients. Genotyping was performed in 745 ESRD patients and 520 control subjects for the angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C gene polymorphisms using polymerase chain reaction and gel analysis. Allele and genotype frequencies of the ACE polymorphism did not differ significantly between ESRD patients and controls. The patient group showed an increased frequency of the T allele of the AGT polymorphism (P = 0.02) and the C allele and CC genotype of the AT1R polymorphism (P<0.01). There was an association of the AT1R gene polymorphism with the progression of renal disease to end-stage failure. The time from diagnosis to the onset of ESRD was significantly shorter in patients carrying the C allele than in subjects with the homozygous AA genotype (4.7 years vs 12.6 years, P<0.001). The observed effect was not associated with hypertension in studied subjects. The results of our study demonstrate the association between the AT1R A/C polymorphism and renal disease progression. The CC/AC genotype of this polymorphism might serve as a predictor for early ESRD and might be useful in planning therapeutic strategies for individual patients.

Peripheral vascular disease in Type 2 diabetic Chinese patients: associations with metabolic indices, concomitant vascular disease and genetic factors.

Conventional and genetic risk factors have been reported to play a role in the pathogenesis of vascular disease, but do not explain the lower burden of cardiac and peripheral vascular disease (PVD) in Chinese compared with Caucasians. The role of renin-angiotensin system (RAS) gene polymorphisms and conventional vascular risk factors has not been determined. A total of 3097 Chinese diabetic subjects were screened for PVD, which was identified in 194 of the 2967 patients with Type 2 diabetes. Biochemical parameters and the genotype and allele frequencies of three RAS gene polymorphisms, the angiotensin-converting enzyme (ACE) insertion/deletion, angiotensinogen (AGT) M235T and angiotensin II type 1 receptor (AT1R) A1166C polymorphisms were then compared between the PVD patients and 1046 age, gender and diabetes duration-matched patients without PVD. PVD identified in 6.5% was associated with significantly worse glycaemic control, lipid profile and renal function. Smoking was more common, as were the other macro- and microvascular diseases. The prevalence of hypertension was similar between the groups, yet diastolic blood pressure was slightly lower in the PVD group. The ACE D allele was significantly more frequent in patients with PVD compared with the matched diabetic controls (38.1 vs. 29.8%, P = 0.039). No differences in the AT1R or AGT polymorphisms were observed. PVD was associated with a worse metabolic profile and greater concomitant vascular disease than controls. The ACE I/D polymorphism was associated with PVD in these Type 2 diabetic patients.

Association of the anti inflammatory action of interleukin 10 with metalloproteinases and other inflammatory markers in acute coronary syndromes

In Marfan syndrome, the mitral valve prolapse, ranging from nonclassic to classic form on the basis of the leaflet thickness, is a common condition characterized by a highly variable structural abnormality. We investigated the role of angiotensinogen (AGT) M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor (AT1R) A1166C polymorphisms in influencing the susceptibility to classic or non-classic mitral valve prolapse in Marfan patients.We studied 135 Marfan patients with mitral valve prolapse, diagnosed by echocardiography. AGT, ACE, and AT1R polymorphisms were identified by polymerase chain reaction-based restriction analysis.The frequency of the ACE D, but not AGT 235T and AT1R 1166C allele, was significantly higher in patients with classic mitral valve prolapse in comparison to that observed in the non-classic one (p = 0.03). The percentage of subjects with the contemporaneous presence of ACE D and AGT 235T alleles was significantly higher in the classic mitral valve prolapse group in comparison to the non-classic one (79% vs. 55%, respectively; p = 0.008). The concomitant presence of these two alleles was associated with increased susceptibility to the classic mitral valve prolapse ( OR 3.02, p = 0.016).Our findings show a possible role of ACE and AGT genes as predisposing factors to classic mitral valve prolapse in Marfan patients, thus suggesting a role of renin angiotensin system genes in modulating mitral valve abnormality, and the need for an interventional study with angiotensin II type 1 receptor antagonists, which considers the leaflet thickness progression in Marfan patients with MVP.

ACE and angiotensin II and nonarteritic anterior ischemic optic neuropathy: Author reply

Dr. Donahue’s letter expresses concerns that in our article, “The Role of Angiotensin Converting Enzyme and Angiotensin II Type 1 Receptor Gene Polymorphisms in Patients with Nonarteritic Anterior Ischemic Optic Neuropathy (NAION),” further statistical analysis are required to support our conclusion that angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) have no role in the pathogenesis of the disease. The insignificant P values in our study could result from true lack of effect or from small sample sizes and, consequently, low power. We have carried out the power calculations requested by Dr. Donahue with respect to a 20% absolute difference in the allele frequencies of the presumed risks (D allele in the case of ACE and C allele in the case of AT1R). The calculations were based on the use of a two-sided 5% test. The power to detect a 20% difference in ACE and AT1R was 98.7% and 95.2%, respectively. More cogent is a computation of the 95% confidence intervals (CI) for the differences in the D and C allele frequencies (NAION patients minus controls). The 95% CI for the D allele of ACE was −14.9, 6.5 and for the C allele of AT1R, was −3.3, 16.4. For both polymorphisms, the 95% CI indicated small differences; and it ruled out a 20% increment among NAION patients over the controls. Thus, additional calculations support our conclusion that ACE and AT1R polymorphisms have no role in the pathogenesis of NAION.

Angiotensin II type 1 receptor A1166C polymorphism in relation to incident cardiovascular events, hypertension, and blood pressure control in elderly Caucasians and African Americans

P17 Objective: The C allele of the angiotensin II type 1 receptor (AT1R) A1166C polymorphism has been associated in several studies with increased risks of hypertension (HTN) and myocardial infarction (MI), and with enhanced blood pressure (BP) response to ACE inhibitors but not calcium antagonists. Most of these studies were small, and none included large numbers of African Americans. We examined these associations in the Cardiovascular Health Study, an observational cohort study of risk factors for coronary disease and stroke in men and women ≥ 65 years of age. Methods: All 771 self-identified African Americans plus 1333 randomly-selected Caucasians were genotyped for the AT1R polymorphism. BP, medication use, and HTN were assessed annually. Incident MI/coronary death (CHD, n = 125 in whites; n = 60 in blacks), incident total cardiovascular events (CVD, n = 226 in whites; n = 101 in blacks), incident congestive heart failure (CHF, n = 146 in whites; n = 55 in blacks), and incident HTN (n = 184 in whites; n = 85 in blacks) were identified during up to 8 years of follow-up. Results: Genotype frequency distributions differed between whites (AA 49%, AC 41%, CC 10%) and blacks (85%, 15%, 1%, p &lt; 0.0005). Age, gender or HTN at baseline did not differ by genotype in either group. In both whites and blacks, genotype was not associated with incident CHD (HR for AC/CC vs. AA, 95% CI in whites = 1.0, 0.7-1.5; blacks, HR = 0.7, 0.3-1.5), incident total CVD events (whites, HR = 1.0, 0.8-1.3; blacks, HR = 0.9, 0.5-1.6), incident CHF (whites, HR = 1.1, 0.8-1.5; blacks, 0.6, 0.3-1.4) or newly-identified HTN (whites, HR = 0.8, 0.6-1.1; blacks, HR = 1.1, 0.6-1.9). Among treated hypertensives, the association of genotype with controlled BP (&lt;140/&lt;90) did not differ between users of calcium channel blockers and users of ACE inhibitors in either race. Conclusion: In this large population-based elderly cohort, the AT1R A1166C polymorphism was not associated with prevalent or newly-identified HTN, incident CVD events, or BP response to antihypertensive agents in either Caucasians or African Americans.

The role of angiotensin converting enzyme and angiotensin ii type 1 receptor gene polymorphisms in patients with nonarteritic anterior ischemic optic neuropathy

Objective To determine the role of angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) polymorphisms in the pathogenesis of nonartertic anterior ischemic optic neuropathy (NAION). Design Retrospective, case-control study. Participants Seventy-four patients with NAION diagnosed from 1984 through 1999. Seventy-one patients who visited the Eye Institute comprised the control group. Testing intervention DNA was extracted from whole blood obtained from all patients and control participants. Polymerase chain reaction (PCR) was used for analysis of ACE and AT1R polymorphisms. Results The frequency of the polymorphism for ACE among the NAION patients (39.2% deletion allele [DD], 54.0% deletion/insertion [D/I] locus, 6.8% insertion allele [II]) was similar to that of the control group (50.7% DD, 39.4% D/I, 9.9% II), with P = 0.21. The frequency of the polymorphism of AT1R in the NAION patients was 5.4% CC, 44.6% CA, 50% AA, and in the control group it was 4.2% CC, 33.8% CA, 62.0% AA, with P = 0.35. Participants less than 55 years of age and those more than 55 had quite similar distributions. Conclusions Angiotensin converting enzyme and AT1R polymorphisms have no part in the mechanism of NAION. Thus drugs such as ACE inhibitors or AT1R antagonists are not specifically indicated for treatment of these patients.

Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphisms: association with early coronary disease.

To examine the association between coronary artery disease and polymorphisms at the angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) genes. A total of 181 patients younger than 50 years and 240 controls from the same homogeneous Caucasian population (Asturias, Northern Spain) were genotyped (using polymerase chain reaction) for the ACE insertion/deletion (ACE-I/D) and the AT1R A/C transversion (AT1R-A/C) (3-untranslated region) polymorphisms. The DD-genotype was at a non-significant higher frequency among patients (50%) than in controls (41%). No difference between the two groups was found for the AT1R-genotypes. Distribution of ACE-genotypes according to AT1R-genotypes showed a significant association between ACE-DD and AT1R-CC and early coronary disease. Among the CC patients 58% were DD, compared to 21% among the controls (p = 0.02; OR = 5.32, 95% CI = 1.45, 19.51). We determined the distribution of these genotypes among the hypertensive and non-hypertensive patients. Frequencies of ACE- or AT1R-genotypes did not differ between the two groups. However, we found an interaction between the DD- and CC-genotypes in the group of normotensives. Among the CC patients, 13% of the hypertensives and 75% of the normotensives were DD (p = 0.014). Our results indicate a synergistic contribution of ACE and AT1R polymorphisms to the risk of coronary artery disease. This gene-gene interaction could have clinical implications. Approximately 2% of individuals in our population are CC + DD, and the genotyping of both polymorphisms could identify those with a high relative risk for coronary artery disease.