Journal of the Renin-Angiotensin-Aldosterone System

The aim of this study was to investigate whether MiR-30a regulates autophagy by regulating the Beclin-1 protein, which is the marker for autophagosomes during myocardial injury, when induced by angiotensin II (Ang II).

We randomly assigned 20 rats into two equal groups: Control group and Ang II group. We detected the expression of MiR-30a by quantitative real-time polymerase chain reaction (RT-PCR), and we employed western blotting to detect the protein expression of Beclin-1.

In this study, we found that Ang II induced cardiomyocyte autophagy, together with down-regulation of MiR-30a and upregulation of the Beclin-1 protein. We also found that the Beclin-1 protein is regulated by MiR-30a, by transferring a MiR-30a mimic or AMO-204 into the cardiomyocytes.

These studies provided evidence that MiR-30a plays an important role in regulating autophagy through the Beclin-1 protein, during myocardial injury induced by Ang II.

Adrenergic receptors (AR) play important roles in regulating lung function. However, there are few reports concerning AR expression and the protective effect of angiotensin II receptor blockers (ARB) on the lung in chronic heart failure (CHF). In this study, we aimed to investigate the protective effects of the ARB olmesartan on the lung in CHF.

Wistar rats were randomly divided into four groups: normal control, sham-operated rats, rats with CHF induced by ligating the left anterior descending coronary arteries, and rats with CHF treated with olmesartan (1 mg/kg) once daily for 8 weeks. Heart function, plasma renin activity (PRA) and angiotensin II (Ang II) levels, lung microscopic structure inspection and mRNA and protein expressions of α_1A-, β₁- and β₂-AR in lung were tested.

Compared with the CHF group, PRA and Ang II levels were decreased while heart function and mRNA and protein expression of α_1A-AR, β₁-AR and β₂-AR were up-regulated in the olmesartan group (p<0.05 or p<0.01). The inflammation and cell proliferation in CHF lung tissue were reduced in the olmesartan group.

Olmesartan may play a beneficial role in protecting lung in CHF by up-regulating AR and decreasing levels of PRA and Ang II.

The nuclear factor-κB (NF-κB) is an important regulator of the inflammatory response. Angiotensin II (Ang II) activates the NF-κB pathway linked to renal inflammation. Although both AT₁ and AT₂ receptors are involved in Ang II-mediated NF-κB activation, the biological processes mediated by each receptor are not fully characterized. Interleukin-1β (IL-1β) is an important macrophage-derived cytokine that regulates immune and inflammatory processes, activating intracellular pathways shared with Ang II, including the NF-κB.

In vitro studies were done in primary cultured rat mesangial cells. NF-κB pathway was evaluated by phosphorylated levels of p65/IκB and DNA binding activity. The Ang II receptor subtype was determined by pretreatment with AT₁ and AT₂ antagonists.

In mesangial cells the simultaneous presence of Ang II and IL-1β caused a synergistic activation of the NF-κB pathway and a marked upregulation of proinflammatory factors under NF-κB control, including monocyte chemoattractant protein-1. The AT₁, but not AT₂, antagonist abolished the synergistic effect on NF-κB activation and proinflammatory genes caused by coincubation of Ang II and IL-1β.

These data indicates that Ang II, via AT₁/NF-κB pathway activation, cooperates with IL-β to increase the inflammatory response in mesangial cells.

The present study investigates, in 23-day-old and adult male rats, the effect of severe food restriction in utero on blood pressure (BP), and its association with nephron structure and function changes, angiotensin II (AT1R/AT2R), glucocorticoid (GR) and mineralocorticoid (MR) receptor expression.

The daily food supply to pregnant rats was measured and one group (n=15) received normal quantity of food (NF) while the other received 50% of that (FR50%) (n=15). Kidneys were processed to AT1R, AT2R, MR, and GR immunolocalization and for western blotting analysis. The renal function was estimated by creatinine and lithium clearances in 12-week-old offspring.

By stereological analyses, FR50% offspring present a reduction of nephron numbers (35%) with unchanged renal volume. Expression of AT1R and AT2R was significantly decreased in FR50% while the expression of GR and MR increased in FR50%. We also verified a pronounced decrease in urinary sodium excretion accompanied by increased BP in 12-week-old FR50% offspring.

The current data suggest that changes in renal function are conducive to excess sodium tubule reabsorption, and this might potentiate the programming of adult hypertension. It is plausible to arise in the current study an association between decreasing natriuresis, reciprocal changes in renal AngII and steroid receptors with the hypertension development found in FR50% compared with age-matched NF offspring.

The current study considers changes of the postnatal brainstem cell number and angiotensin receptors by maternal protein restriction (LP) and LP taurine supplementation (LPT), and its impact on arterial hypertension development in adult life.

The brain tissue studies were performed by immunoblotting, immunohistochemistry, and isotropic fractionator analysis. The current study shows that elevated blood pressure associated with decreased fractional urinary sodium excretion (FE_Na) in adult LP offspring was reverted by diet taurine supplementation. Also, that 12-day-old LP pups present a reduction of 21% of brainstem neuron counts, and, immunohistochemistry demonstrates a decreased expression of type 1 angiotensin II receptors (AT₁R) in the entire medial solitary tract nuclei (nTS) of 16-week-old LP rats compared to age-matched NP and LPT offspring. Conversely, the immunostained type 2 AngII (AT₂R) receptors in 16-week-old LP nTS were unchanged.

The present investigation shows a decreased FE_Na that occurs despite unchanged creatinine clearance. It is plausible to hypothesize an association of decreased postnatal nTS cell number, AT₁R/AT₂R ratio and FE_Na with the higher blood pressure levels found in taurine-deficient progeny (LP) compared with age-matched NP and LPT offspring.

The purpose of this study was to determine the relative expression of clinically-relevant components of the renin-angiotensin system (RAS) in the adult human eye.

We obtained 14 post-mortem enucleated human eyes from patients whom had no history of inflammatory ocular disease nor pre-mortem ocular infection. We determined the gene expression for prorenin, renin, prorenin receptor, angiotensin-converting enzyme, angiotensinogen and angiotensin II Type 1 receptor, on tissue sections and in cultured human primary retinal pigment epithelial and iris pigment epithelial (RPE/IPE) cell lines, using both qualitative and quantitative reverse transcription polymerase chain reaction (RT-PCR). Protein expression was studied using indirect immunofluorescence (IF).

Almost all components of the classical RAS were found at high levels, at both the transcript and protein level, in the eyes’ uvea and retina; and at lower levels in the cornea, conjunctiva and sclera. There was a much lower level of expression in the reference cultured RPE/IPE cells lines.

This study describes the distribution of RAS in the normal adult human eye and demonstrates the existence of an independent ocular RAS, with uveal and retinal tissues showing the highest expression of RAS components. These preliminary findings provide scope for examination of additional components of this system in the human eye, as well as possible differential expression under pathological conditions.

Perivascular adipose tissue is implicated in vasoreactivity; however, its effect on atherosclerosis remains undefined.

We examined the effect of a high-cholesterol diet (HCD) on phenotypic alterations of the thoracic periaortic adipose tissue (tPAT) in apoE-deficient (apoE^–/–) mice. Gene expression of the components of the renin angiotensin system and that of macrophage markers were significantly higher in apoE^–/– mice fed an HCD than in those fed a chow diet (CD). These changes were absent both in angiotensin II (AngII) receptor blocker (ARB)-treated apoE^–/– mice and in Ang II type 1 (AT₁) receptor-deficient apoE^–/– (Agtr1^–/–/apoE^–/–) mice. To evaluate their effect on atherosclerosis, we transplanted tPAT into apoE^–/– mice alongside the distal abdominal aorta. Transplanted tPAT was harvested from apoE^–/– and Agtr1^–/–/apoE^–/– mice fed a CD (tPAT-CD/apoE^–/–, tPAT-CD/Agtr1^–/–/apoE^–/–), HCD (tPAT-HCD/apoE^–/–, tPAT-HCD/Agtr1^–/–/apoE^–/–), or HCD in combination with ARB treatment (tPAT-HCD/ARB/apoE^–/–). Four weeks after transplantation, a significantly increased oil red O-positive area was observed in the aorta of tPAT-HCD/apoE^–/– mice than in tPAT-CD/apoE^–/– mice. Such a change was absent in tPAT-HCD/ARB/apoE^–/– and tPAT-HCD/Agtr1^–/–/apoE^–/– mice.

Our findings demonstrated that AT₁ receptor plays a crucial role in HCD-induced phenotypic alterations of tPAT, modulation of which could exert beneficial effects on atherosclerosis.

Cardiac hypertrophy in myocytes is in part regulated by changes in expression of a novel Ang II type 2 receptor (AT2-receptor) interacting protein identified as ATIP.

The role of the AT2-receptor in cardiac hypertrophy is controversial, with some reports indicating that AT2-receptor activation has detrimental effects on disease progression, whereas others indicate that it has a beneficial role.

In an effort to unravel this paradox, we examined the expression and function of ATIP in cell-based models of cardiac hypertrophy using QPCR, immunohistochemistry, cell proliferation, morphological and transfection techniques in H9c2 cardio-myoblast and myotubules.

These studies indicate that in cultured cardio-myoblast and myotubules, Ang II mediates cellular hypertrophy and proliferation solely via the AT1-receptor, the ATIP variants are abundantly expressed and that ATIP3 may play an anti-proliferative/hypertrophic role in these cells in the absence of AT2-receptor expression or activation.

Previously ATIP has been shown to inhibit growth factor signalling in cancerous cells via an interaction with the AT2-receptor. This is the first report to identify that ATIP may have a similar role in other disease states characterised by excessive growth and indicates that for ATIP3, at least, an interaction with the AT2-receptor may not be necessary.

We studied the effects of angiotensin type 1 receptor blockade (ARB) on formation of new cardiomyocytes, neovascularization and ventricular remodelling after myocardial infarction (MI).

Male Wistar rats with MI or sham-operated controls were treated with either losartan or vehicle. Bromodeoxyuridine (BrdU) was given to identify newly formed cardiac cells. Immunohistochemical analysis was used to quantify proliferative and apoptotic cardiomyocytes, vascular structures and c-Kit+ stem/progenitor cells, western blotting to evaluate gene expression, and planimetry and echocardiography to assess cardiac structure and function.

The number of BrdU+ cardiomyocytes increased similarly in the vehicle and losartan treated MI groups. The number of apoptotic or proliferating cardiomyocytes did not differ between losartan and vehicle treated rats. Losartan induced an increase in capillary and BrdU+ vascular densities in the infarct border zone. Losartan treatment completely prevented post-MI cardiac hypertrophy. In the non-infarcted myocardium the amount of all BrdU+ cells (including non-cardiomyocyte cells) was highest in the vehicle treated MI rats at week 4.

The number of newly formed cardiomyocytes increased after MI. Angiotensin II blockade neither stimulated nor prevented cardiomyocyte regeneration. ARB treatment increased vascular densities in the infarct border zone and modulated remodelling of the non-infarcted myocardium preventing effectively post-MI cardiac hypertrophy.

The present study was designed to investigate the effect of ramipril (angiotensin-converting enzyme inhibitor) on the chronic constriction injury of sciatic nerve induced neuropathic pain in mice.

The neuropathic pain was induced by four loose ligations of the right sciatic nerve in mice. The battery of behavioral tests, i.e. plantar, pin prick, tail flick, tail pinch, rota rod tests, were performed to assess the degree of thermal and mechanical hyperalgesia in ipsilateral paw and tail, and motor in-coordination activity respectively. In addition, the biochemical tests, i.e. total protein, thiobarbituric acid reactive substances and reduced glutathione, were also performed in sciatic nerve tissue samples.

The administration of ramipril (2 and 4 mg/kg, p.o.) significantly attenuated chronic constriction injury-induced rise in peripheral as well as central pain sensitivity (thermal and mechanical) along with impairment of motor in-coordination activity. Further, it also produces ameliorative effects on chronic constriction injury-induced rise in thiobarbituric acid reactive substances and decrease in glutathione levels when compared with a normal control group.

It may be concluded that angiotensin-converting enzyme inhibitor may be a potential new target for the management of neuropathic pain.

Inhibitors of the renin–angiotensin aldosterone system (RAAS) are the basic drugs for treatment of diabetic nephropathy, as to some extent is spironolactone. The aim of the study was to evaluate the effect of spironolactone versus spironolactone plus hydrochlorothiazide in decreasing proteinuria in type 2 diabetic mellitus (T2DM) patients.

In a double-blind clinical trial, 60 T2DM patients with nephropathy randomly assigned to three equal groups were enrolled. Spironolactone (50 mg/day) plus placebo, spironolactone (50 mg/day) plus hydrochlorothiazide (25 mg/day), and hydrochlorothiazide (25 mg/day) plus placebo were prescribed, respectively. The duration of treatment was three months for all patients. Urine protein was measured at the beginning and end of the study and analysis of data was performed.

Twenty-six of the patients were male, with a total mean age of 56.8±8.3 years. Mean 24-h urine protein was reduced in patients in groups 1 and 2 compared to the third group (p < 0.001). Serum potassium in the first group showed a significant increase of 0.26 meq/lit with mean 4.64 ± 0.28 meq/lit (p=0.002), but it did not change in the second and third groups.

Our results showed that spironolactone plus hydrochlorothiazide is an effective and inexpensive modality in the treatment of diabetic nephropathy without increasing serum potassium.

Several studies have definitively shown the benefit of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure (HF). However, very few prior studies examined the relationship between the timing of initiation of MRAs and prognosis. In addition, on this topic, there is no information regarding the specific population of patients suffering a first episode of decompensated congestive HF.

We studied a homogenous cohort of patients discharged alive from our hospital after a first episode of decompensated congestive HF, in order to clarify the association between time of aldosterone receptor antagonist (ARA) initiation (within the first 90 days after hospital discharge) and mortality. Our population was composed of a series of consecutive patients. All-cause mortality was compared between patients who initiated MRAs at discharge (early group) and those who initiated MRAs one month later and up to 90 days after discharge (delayed group). We used prescription time distribution matching to control for survival difference between groups.

The early and delayed groups consisted of 365 and 320 patients, respectively. During the one-year follow-up, a significant difference in mortality was demonstrated between groups. Adjusted hazard ratios (HRs) for early versus delayed initiation were 1.72 (95% confidence interval (CI) 0.96 to 2.84) at six months, and 1.93 (95% CI 1.18 to 3.14) at one year.

Delay of MRA initiation up to 30 to 90 days after discharge implies a significant increase in mortality compared with MRA initiation at discharge, after a first episode of decompensate congestive HF.

The objective of this paper is to investigate a profile on circulatory renin−angiotensin system (RAS) activity in hypercholesterolemic (HC) patients treated with statins.

Eighteen primary HC patients and 18 sex- and age-matched healthy adults were included in this study as controls. Total cholesterol (TC), triglyceride (TG), LDL-C, blood glucose, angiotensin-converting enzyme (ACE) activity, and angiotensin II (Ang II) levels were measured before and four and eight weeks after beginning statin treatment in the HC group. Similar measurements were taken in the control group at baseline.

At baseline, TC, TG and LDL-C levels, as well as ACE activity and Ang II concentrations, were significantly higher in the HC group than in the control group. Based on the baseline data collection of 36 participants, there were significant positive correlations between ACE activity and TC (r = 0.54) or LDL-C (r = 0.51), and between Ang II level and TC (r = 0.34) or LDL-C (r = 0.27). TC, LDL-C, Ang II (35.46±14.49 vs 71.10±20.47 pg/ml, p < 0.05) levels and ACE activity (108.9±51.9 vs 180.1±71.3 U/L, p < 0.05) were decreased in HC patients eight weeks after starting statin treatment. In HC patients, RAS activity correlated positively with TC and LDL-C levels before and after treatment.

In HC patients, lowering serum cholesterol with statins is associated with decreased circulatory RAS activity.

Compared to patients with similar levels of hypertension, patients with primary aldosteronism have a greater left ventricular hypertrophy (LVH). The presence of LVH should be detected as early as possible to prevent cardiovascular complications associated with the condition. We evaluated comparative diagnostic value of electrocardiographic (ECG) indexes for LVH in patients with primary aldosteronism.

ECG and echocardiographic data were obtained in 88 patients with primary aldosteronism. We analyzed the four most commonly used ECG indexes, including Sokolow-Lyon index, Cornell voltage index, Cornell product index, and Gubner index.

Echocardiographic LVH was found in 35 patients (40%). Sensitivity ranged from 0% for Gubner index to 49% for Cornell product index. Specificity ranged from 81% for Sokolow-Lyon index to 100% for Gubner index. Sokolow-Lyon index (r=0.43, p<0.001), Cornell voltage index (r=0.55, p<0.001) and Cornell product index (r=0.52, p<0.001) correlated significantly with left ventricular mass (LVM) index. No significant correlation was found between Gubner index and LVM index.

ECG indexes had a reasonably high specificity, but a low sensitivity for LVH in patients with primary aldosteronism. Cornell voltage index and Cornell product index had a better diagnostic value of LVH, and had a better correlation with LVM index in these patients.

The objective of this article is to measure serum dehydroepiandrosterone sulfate (DHEA-S) concentration in both genders with primary aldosteronism (PA).

The study enrolled 78 subjects with normal controls, 46 subjects with essential hypertension and 85 subjects with PA from October 2007 to June 2011. Subjects with PA were divided into three subtype groups: aldosterone-producing adenoma (APA), bilateral idiopathic hyperplasia (IHA) and PA with negative imaging findings.

Women with PA (n = 49) had lower serum DHEA-S levels compared with normal controls and subjects with essential hypertension (p < 0.01). In subtype analysis, only female APAs had lower serum DHEA-S levels (p < 0.01 compared with normal controls, p < 0.01 compared with subjects with essential hypertension). In APA, a significant correlation between tumor size and serum DHEA-S was found in women (p < 0.01).

Our data suggested that serum DHEA-S levels are lower in women with PA. In subtype groups, only women with APA had lower serum DHEA-S. There was no significant difference between subjects with bilateral essential hyperplasia, PA with negative imaging findings, normal controls and subjects with essential hypertension in both genders. The serum DHEA-S level is negatively correlated with the size of APA.

Reduction of blood pressure and proteinuria by blockade of the renin-angiotensin-aldosterone system (RAAS) has been the cornerstone of renoprotective intervention for patients with chronic kidney disease (CKD) for many years.

The aims were to check the use of angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs) in CKD patients.

This was a retrospective, cross-sectional study analysing data from medical records of patients who received specialist care in 1996, 2001, 2006, 2011 in the Outpatient Unit.

The numbers of CKD subjects included in the four independent surveys were as follows: 190, 490, 1799, 1696. The usage of RAAS blocking agents overall increased significantly in subsequent years as follows: 25, 49, 63, 74%. Patients with proteinuria and cardiovascular complications and/or diabetes were receiving RAAS blocking agents more commonly than others. The use of ACEI and/ or ARB in stage 4–5 CKD increased in subsequent years. In 2011 dual RAAS blockade was used in 10% CKD patients overall and 19% patients presented proteinuria.

The use of RAAS blocking agents were increasing in CKD patients under specialist care between 1996–2011. The quality of the management was gradually improved.

To determine if the serum prorenin level is useful for detecting ocular disease in a non-diabetic population.

We enrolled non-diabetic men (n = 402) and women (n = 349) in our study. We used the antibody-activating direct enzyme kinetic assay of human prorenin to determine serum prorenin levels. We performed multiple regression analysis to determine the factors that affect serum prorenin levels, such as: age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, fasting blood sugar, and HbA1c or estimated glomerular filtration rate. Our study subjects were divided into groups by their ophthalmologic diagnosis. One-way analysis of variance (ANOVA) was performed to detect a significant difference in the serum prorenin levels among the groups.

There were no significant differences in serum prorenin levels among the ocular diseases and disorders. The DBP was negatively correlated with serum prorenin levels in men (r = − 0.1992; p = 0.021) and in women (r = − 0.2067; p = 0.031).

Considering the current results and those of previous studies together, we found that the prorenin value is useful solely for predicting development of diabetic retinopathy in adults.

Angiotensin-converting enzyme 2 (ACE2) is a member of the renin–angiotensin system that degrades angiotensin (Ang) II to the seven-amino acid peptide fragment Ang-(1-7). We evaluated the changes in urinary ACE2 levels in response to treatment with the angiotensin II type 1 receptor blocker olmesartan in diabetes patients with nephropathy.

This prospective, open-label, interventional study was conducted with 31 type 2 diabetes patients with nephropathy. After initial evaluation, patients received 20 mg/day olmesartan, which was increased to 40 mg/day over a 24-week period.

In diabetes patients with chronic kidney disease, olmesartan significantly increased urinary ACE2 levels independently of blood pressure and plasma aldosterone levels and reduced albuminuria, urinary liver-type fatty acid binding protein (L-FABP), and plasma aldosterone levels. Multivariable regression analysis revealed that the change in urinary L-FABP levels was an independent predictor of increased urinary ACE2 levels.

Olmesartan may have the unique effect of increasing urinary ACE2 levels. However, whether this contributes to olmesartan’s renoprotective effect must be examined further.

Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang

Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi:10.1177/1470320314563426

Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou

Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi:10.1177/1470320314563424

Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou

Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi:10.1177/1470320314566019

Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang, and Hong-Yan Li

Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population

Journal of Renin-Angiotensin-Aldosterone System 1470320314563425, first published on February 1, 2015 doi:10.1177/1470320314563425

Chun-Hua Yang and Tian-Biao Zhou

Relationship between the angiotensinogen A1166C gene polymorphism and the risk of diabetes mellitus developing into diabetic nephropathy

Journal of Renin-Angiotensin-Aldosterone System 1470320314566221, first published on February 1, 2015 doi:10.1177/1470320314566221

Chun-Hua Yang and Tian-Biao Zhou

Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression

Journal of Renin-Angiotensin-Aldosterone System 1470320314568521, first published on February 3, 2015 doi:10.1177/1470320314568521

Guohui Liu, Tian-Biao Zhou, Zongpei Jiang, and Dongwen Zheng

Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population

Journal of Renin-Angiotensin-Aldosterone System March 2015 16: 165-171, first published on November 14, 2014 doi:10.1177/1470320314557849

Weiqiang Zhong, Zhongliang Huang, Yong Wu, Zongpei Jiang, and Tian-Biao Zhou

Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy

Journal of Renin-Angiotensin-Aldosterone System September 2015 16: 660-665, first published on August 20, 2014 doi:10.1177/1470320314524011

Bahrain has a high prevalence of type 2 diabetes mellitus (T2DM). Previously, Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism was found to be associated with T2DM in Bahrainis. The relationship between the disease progression in Bahraini T2DM population and the genetic polymorphism of methylene-tetrahydrofolate-reductase (MTHFR) C677T is still under investigation.

The current study investigated the distribution of MTHFR C677T gene polymorphism among Bahraini T2DM patients and examined the interaction between ACE I/D and MTHFR C677T polymorphisms on the risk of developing T2DM and its long-term complications.

Polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP) were used to test for the presence of ACE I/D and MTHFR C677T polymorphisms in 171 patients with T2DM compared to 188 healthy (non-diabetic) age-matched control subjects from Bahrain.

The incidence of the DD genotype and D allele of the ACE gene was high among Bahraini T2DM patients. MTHFR allele and genotype frequencies did not differ between patients and controls. No significant relationship was identified between the combinations of ACE I/D and MTHFR C677T polymorphisms with T2DM.

The results clearly showed an association of the ACE I/D polymorphism with the progression of T2DM, but when it interacts with MTHFR polymorphism no influence was detected on the increased risk of T2DM.

Previous studies have reported the relation between the adiponectin polymorphisms and the risk of ischemic stroke. However, the findings is inclusive. In the present study, we performed a meta-analysis to clarify the relation between the adiponectin polymorphisms and the stroke.

Relevant studies were identified by searching PubMed, EMBASE, ISI Web of Science, ScienceDirect, Wiley Online Library, Wanfang database in China, and Chinese National Knowledge Infrastructure databases (CNKI) through July 2013 and other method such as reviewing the reference of retrieved literatures. We selected literatures that reported Odds ratio (OR) and 95% confidence interval (CI) for the relation between the ischemic stroke and the adiponectin genetic polymorphisms. With 1720 stroke cases and 5549 controls, were included. Our results showed that rs2241766 was associated with the risk of ischemic stroke in a recessive model (GG vs (TT+TG), OR = 1.29, 95% CI: 1.01–1.64, p = 0.04). However, rs1501299 and rs266729 were not found to be associated with ischemic stroke in our analysis.

The present study suggested that rs2241766 polymorphism of adiponectin gene was associated with the risk for ischemic stroke.

The aldosterone synthase (CYP11B2)-344T>C gene polymorphism has been reported to influence the risk of atrial fibrillation (AF) in many studies; however, the results remain controversial and ambiguous.

We therefore carried out a meta-analysis of published case-control studies to investigate the association between CYP11B2-344T>C polymorphism and AF susceptibility. Electronic searches were conducted on links between this variant and AF in several databases. Odds ratios (ORs) and 95% confidence intervals (CIs) for homozygous, dominant model, recessive model and allele were calculated to estimate the strength of associations in fixed and random effect models. Heterogeneity and publication bias were also assessed.

A total of nine case-control studies were identified. The C allele was associated with an increased susceptibility risk of AF compared with the T allele among hypertension populations (OR=1.26; 95% CI=1.09–1.45). The contrast of homozygotes and the recessive model produced the same pattern of results as the allele contrast. In the hypertension population, a significant association was found for the genetic models that were examined.

Our pooled data suggest a significant association exists between CYP11B2-344T>C polymorphism and AF among hypertension populations.

Angiotensin-converting enzyme (ACE) I/D polymorphism has been reported to be associated with lung cancer, but the results of previous studies are conflicting. The present study was designed to investigate the association between this polymorphism and the risk of lung cancer using a meta-analysis of the published studies.

Two investigators independently searched the PubMed, Embase and CNKI databases. This meta-analysis covered six case-control studies, including 807 lung cancer patients and 816 healthy controls.

The results of this meta-analysis based on all the studies showed no significant association between ACE I/D gene polymorphism and lung cancer risk (DD vs II: OR = 1.18, 95% CI = 0.68–2.04; DI vs II: OR = 0.93, 95% CI = 0.56–1.53; DD+DI vs II: OR = 1.01, 95% CI = 0.68–1.50; DD vs II+DD: OR =1.11, 95% CI = 0.73–1.71). In the subgroup analysis by race and the larger studies (n > 200 participants), no significant associations between the ACE I/D polymorphism and risk of lung cancer were indicated. However, when the analyses were restricted to small studies (n ≤ 200 participants), a significantly higher risk was observed (DD vs II: OR = 2.57, 95% CI = 1.24–5.30).

This meta-analysis suggests that the ACE gene I/D polymorphism may not be associated with the risk of lung cancer, and the observed increase in the risk of lung cancer may be due to small-study bias.

The purpose of this study was to examine whether the insertion (I) and deletion (D) of angiotensin-converting enzyme (ACE) polymorphism confers susceptibility to psoriasis, vitiligo and rheumatoid arthritis (RA).

A meta-analysis was conducted on the association between the ACE I/D polymorphisms and psoriasis, vitiligo and RA.

Fifteen studies comprising five on psoriasis, five on vitiligo and five on RA were available for the meta-analysis consisting of 2094 cases and 2871 controls. Meta-analysis of the DD+ID genotype showed significant associations with psoriasis (odds ratio (OR) 0.753, 95% confidence interval (CI) 0.601–0.921, p = 0.006). Meta-analysis showed no association between vitiligo and the ACE I/D polymorphism. Meta-analysis of the DD+ID genotype showed an association with RA (OR 2.199, 95% CI 1.379–3.506, p = 0.001). Ethnicity-specific meta-analysis of the D allele showed no association with psoriasis in Europeans, and vitiligo in South Asians. However, subgroup analysis by ethnicity revealed a significant association between the D allele and RA in Arab populations (OR 2.697, 95% CI 1.803–4.034, p = 1.3 × 10⁻⁵).

Our meta-analysis demonstrates that the ACE I/D polymorphism is associated with susceptibility to RA, especially in Arab populations.

Several polymorphisms in the angiotensin-converting enzyme (ACE) and ACE2 genes are associated with the development of end-stage renal disease (ESRD). Certain genetic polymorphisms may modify the deleterious effects of environmental factors such as cigarette smoking and may also modify the inherited risk. We investigated the association of six ACE and ACE2 polymorphisms with ESRD to determine whether a relationship exists between gene–smoking interactions and ESRD.

We performed a case-control association study and genotyped 683 ESRD patients and 653 healthy controls. All subjects were genotyped for ACE (I/D, G2350A and A-240T) and ACE2 (G8790A, A1075G and G16854C) gene polymorphisms by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analysis.

Significant associations were observed between ACE I/D and G2350A polymorphisms and ESRD. There was no difference in ACE2 genotype distribution between ESRD patients and healthy controls. Haplotype analysis showed that DAA and DAT haplotypes were risk factors for ESRD. Moreover, a gene–environment interaction was observed between ACE I/D polymorphism and cigarette smoking.

ACE I/D and ACE G2350A polymorphisms were associated with the development of ESRD. The interaction between ACE I/D polymorphism and smoking is also associated with an enhanced risk of ESRD.

The purpose of this study is to examine whether the insertion (I) and deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) confers susceptibility to aortic aneurysms (AAs).

A meta-analysis was conducted on the associations between the ACE I/D polymorphism and all AAs and abdominal aortic aneurysms (AAAs).

Ten studies consisting of 2784 cases and 2682 controls were available for the meta-analysis. Meta-analysis showed a significant association between the D allele and all types of AA (OR 1.378, 95% CI 1.103–1.723, p = 0.005) and AAA (OR 1.274, 95% CI 1.004–1.617, p = 0.046). Meta-analysis of both the DD genotype and the DD vs. II genotype showed an association with AAAs. Stratification by ethnicity indicated an association between the D allele of the ACE I/D polymorphism and AAAs in Europeans (OR = 1.338, 95% CI = 1.026–1.745, p = 0.031), but not in Asians (OR = 0.927, 95% CI = 0.660–1.303, p = 0.663). Furthermore, analysis using the recessive model, dominant model, and homozygote contrast all showed the same pattern for the D allele.

Our meta-analysis demonstrates that the ACE I/D polymorphism is associated with susceptibility to AAAs in European populations.

The purpose of this study was to examine whether the insertion (I) or deletion (D) of angiotensin-converting enzyme (ACE) polymorphism confers susceptibility to sarcoidosis.

A meta-analysis on the associations between the ACE I/D polymorphism and sarcoidosis was conducted.

Seventeen comparison studies consisting of 1556 cases and 2381 controls were available for the meta-analysis. Meta-analysis revealed a significant association between the D allele and sarcoidosis (OR 1.206, 95% CI 1.049–1.386, p = 0.009). An ethnicity-specific meta-analysis of the DD+ID genotype showed an association with sarcoidosis in East Asians (OR 1.342, 95% CI 1.041–1.729, p = 0.023). An association was found between the DD genotype of the ACE I/D polymorphism and sarcoidosis (OR 1.251, 95% CI 1.070–1.463, p = 0.005). Furthermore, stratification by ethnicity indicated an association between the DD genotype and sarcoidosis in Europeans (OR = 1.215, 95% CI = 1.010–1.462, p = 0.039).

Our meta-analysis demonstrates that the ACE I/D polymorphism is associated with susceptibility to sarcoidosis in European and East Asian populations.