To investigate the role of genetic variants of angiotensin converting enzyme (ACE) and angiotensinogen (AGT) genes in the antiproteinuric efficacy of ACE inhibitor therapy in diabetic nephropathy (DN) patients.

In the present study, 270 type 2 diabetes mellitus patients with nephropathy were enrolled and treated with ACE inhibitor (ramipril) and followed at 6 mo for renal function and albumin excretion by estimating serum creatinine, end stage renal disease, and albumin/creatinine ratio (ACR) in urine. Genotyping of ACE I/D and AGT M235T polymorphisms were performed by using primer specific polymerase chain reaction (PCR) and PCR-RFLP techniques, respectively.

Forty-eight percent of DN patients (responders) benefited with respect to proteinuria from ACE inhibitor therapy at 6 mo follow-up. A significant reduction in ACR was observed after 6 mo treatment with ACE inhibitor irrespective of whether DN patients were micro-albuminuric (≥ 30 and < 300 mg/g creatinine) or macro-albuminuric (≥ 300 mg/g creatinine) at the time of enrollment. However, macro-albuminuric patients (55%) showed better response to therapy. A reduction in urinary ACR was found independent of genotypes of ACE I/D and AGT M235T polymorphisms although macro-albuminuric patients having TT genotype showed statistically insignificant increased response (72%).

ACE inhibitor therapy reduced urinary ACR by ≥ 30% in 50% of DN patients and the response is independent of ACE I/D and AGT M235T polymorphisms.

Hypertension is a multifactorial condition with diverse physiological systems contributing to its pathogenesis. Individuals exhibit significant variation in their response to antihypertensive agents. Traditional markers, such as age, gender, diet, plasma renin level, and ethnicity, aid in drug selection. However, this review explores the contribution of genetics to facilitate antihypertensive agent selection and predict treatment efficacy. The findings, reproducibility, and limitations of published studies are examined, with emphasis placed on candidate genetic variants affecting drug metabolism, the renin-angiotensin system, adrenergic signalling, and renal sodium reabsorption. Single-nucleotide polymorphisms identified and replicated in unbiased genome-wide association studies of hypertension treatment are reviewed to illustrate the evolving understanding of the disease's complex and polygenic pathophysiology. Implementation efforts at academic centers seek to overcome barriers to the broad adoption of pharmacogenomics in the treatment of hypertension. The level of evidence required to support the implementation of pharmacogenomics in clinical practice is considered.

Approximately 20-40% of diabetic patients develop nephropathy which is the leading cause of ESRD in developed countries. The ACE I/D polymorphism is thought to be a marker for functional polymorphism which regulates circulating and tissue ACE activity. While the initial study found a protective effect of the II genotype on the development of nephropathy in IDDM patients, subsequent studies have addressed the role of ACE I/D polymorphism in the development and progression of diabetic nephropathy. RAAS blockers are the first line drugs for the treatment hypertension associated with diabetes and have been widely used in everyday clinical practice for the purpose of reducing proteinuria in patients with various renal diseases. However, the antiproteinuric effect of RAAS blockers is variable and the percentage of reducing proteinuria is in the range of 20-80%. The antiproteinuric effect of RAAS blockers may be related to a number of factors: the type or the dose of RAAS blockers, the duration of therapy, the level of sodium intake, and the type of patient's ACE I/D genotype. Besides the nongenetic factors, drug responses, can be influenced by ACE gene polymorphism. In this review, we discuss the relationship between ACE I/D polymorphism and diabetic nephropathy and therapeutic response of RAAS blockers.

Angiotensin converting enzyme (ACE) gene encodes ACE, a key component of renin angiotensin system (RAS), plays an important role in blood pressure homeostasis by generating the vasoconstrictor peptide angiotensin II.

Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched.

The presence of ACE insertion/deletion (I/D) polymorphism affects the plasma level of ACE. ACE DD genotype is associated with the highest systemic and renal ACE levels compared with the lowest ACE activity in carriers of II genotype.

In this review focus has been performed on the study of ACE I/D polymorphism in various populations and its influence on the risk of onset and progression of diabetic nephropathy. Also, association between ACE I/D polymorphism and response to ACE inhibitor and angiotensin II receptor antagonists will be reviewed. Further, synergistic effect of this polymorphism and variants of some genes on the risk of development of diabetic nephropathy will be discussed.

Only 23 - 41% of hypertensive patients receiving antihypertensive drugs achieve adequate blood pressure control. Multiple physiological systems regulate blood pressure and variation in genes involved in these systems may account for enhanced or diminished blood pressure lowering response to antihypertensive therapy.

We explored explanations for variation in blood pressure response to antihypertensive drugs by linking genetic polymorphisms in renin-angiotensin-aldosterone system (RAAS) genes to antihypertensive drug response on intermediate parameters (e.g., potassium excretion, aldosterone levels). A MEDLINE search (1966 - 2008) was performed to identify publications reporting effects of genetic polymorphisms in the RAAS on antihypertensive drug response with regard to intermediate parameters.

With regard to the ACE insertion/deletion and the angiotensinogen -217G/A polymorphism variation in blood pressure response could be explained by effects on intermediate parameters. However, most studies that were identified with our search varied in study design, population and outcome, which complicate adequate comparisons.

Little evidence is available that explains these pharmacogenetic interactions. In the future, a better understanding of these mechanisms should provide a more solid evidence base for the individualized hypertension treatment based on genetic variation.

The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been shown to be associated with a number of complications of type 2 diabetes.

on the development and progression of albuminuria, however, have remained controversial, with ethnic differences being a potential reason.The present study is the first report to examine Iranian patients.

Patients (322; 162 males) with type 2 diabetes were categorised in this cross-sectional study into the following groups: normoalbuminuria (n=145), microalbuminuria (n=129) and macroalbuminuria (n=48).ACE gen I/D polymorphism genotypes were determined using the polymerase chain reaction method.

s. The distribution of ACE genotypes was significantly different among the groups (p<0.001), with the II genotype decreasing and the DD genotype increasing in frequency with increasing severity of albuminuria. Multivariate regression analysis showed that the ACE genotype did not change the odds of having microalbuminuria versus normoalbuminuria, while the D allele independently increased the odds of having macroalbuminuria versus microalbuminuria approximately threefold (p<0.01).

In Iranian patients with type 2 diabetes, the D allele is associated with progression, but not development, of albuminuria.

The DD genotype of angiotensin-converting enzyme (ACE) has been suggested as a major contributor of diabetic nephropathy in several populations. The purpose of the present study was to determine whether micro/macroalbuminuria is associated with ACE insertion/deletion (I/D) polymorphism in Mexican Mestizos with type 2 diabetes mellitus.

A total of 435 patients with type 2 diabetes mellitus, of whom 233 had albuminuria, were characterized for the ACE I/D polymorphism by the polymerase chain reaction method.

Clinical and biochemical characteristics and frequencies according to DD, ID and II genotypes in patients with and without albuminuria showed no significant differences. However, only females with micro/macroalbuminuria showed higher frequency of a DD genotype than those without albuminuria (27.9%, 21.2% and 10.5%, respectively; P <or= 0.044). In addition, female patients with macroalbuminuria without dialysis showed no significant differences with patients undergoing dialysis.

The ACE DD genotype is a risk factor for the development of renal disease in Mexican Mestizo females with type 2 diabetes, indicating a possible DD genotype-associated sex effect in renal disease.

Despite the huge amount of studies looking for candidate genes, the ACE gene remains the unique, well-characterized locus clearly associated with pathogenesis and progression of chronic kidney disease, and with response to treatment with drugs that directly interfere with the renin angiotensin system (RAS), such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARA). The II genotype is protective against development and progression of type I and type II nephropathy and is associated with a slower progression of nondiabetic proteinuric kidney disease. ACE inhibitors are particularly effective at the stage of normoalbuminuria or microalbuminuria in both type I and type II diabetics with the II genotype, whereas the DD genotype is associated with a better response to ARA therapy in overt nephropathy of type II diabetes and to ACE inhibitors in male patients with nondiabetic proteinuric nephropathies. The role of other RAS or non-RAS polymorphisms and their possible interactions with different ACE I/D genotypes are less clearly defined. Thus, evaluating the ACE I/D polymorphism is a reliable tool to identify patients at risk and those who may benefit the most of renoprotective therapy with ACE inhibitors or ARA. This may guide pharmacologic therapy in individual patients and help design clinical trials in progressive nephropathies. Moreover, it might help optimize prevention and intervention strategies at population levels, in particular, in countries where resources are extremely limited and 1 million patients continue to die every year of cardiovascular or renal disease.

Randomized clinical trials on progression of renal diseases usually include patients according to criteria for BP, renal function, and proteinuria. There are no data showing that this provides groups with similar baseline rates of renal function loss. Accordingly, the impact of preintervention rate of renal function loss (slope) on outcome of studies has not been established.

Preintervention slope was established in 60 of 89 renal patients without diabetes in whom a 4-yr prospective, randomized intervention had been performed (enalapril versus atenolol), and whether (1) preintervention slope was distributed equally over the groups; (2) treatment benefit, defined as slope improvement, corresponded to study outcome; and (3) preintervention slope was a determinant of intervention slope were analyzed.

The preintervention slope was different in the groups: -3.7 +/- 3.2 in the group to receive enalapril versus -2.2 +/- 3.3 ml/min per yr in the group to receive atenolol. The intervention slopes were similar: -1.9 +/- 0.8 enalapril and -1.8 +/- 0.7 ml/min per yr atenolol. Accordingly, slope improved during enalapril only. When analyzed by angiotensin-converting enzyme (I/D) genotype, slope improvement was found only in DD genotype. On multivariate analysis, the preintervention slope was a main predictor of the intervention slope.

Differences in preintervention slope are relevant to outcome of trials and can induce bias. For future studies, allocation according to preintervention slope, although time-consuming, may be useful to allow conduction of more valid studies in a smaller number of patients.

The authors hypothesized that genetic predisposition to diabetes complications would be more evident among low-risk individuals and aimed to identify genes related to developing complications (confirmed distal symmetric polyneuropathy, overt nephropathy, or coronary artery disease) in low-risk groups. Participants in the Pittsburgh, Pennsylvania, Epidemiology of Diabetes Complications Study of childhood-onset type 1 diabetes, first seen in 1986-1988 (mean age, 28 years; diabetes duration, 19 years), were reexamined biennially for 10 years. For each complication, subgroups with the lowest disease risk were identified by using tree-structured survival analysis, and 15 candidate genes were compared between subjects with and without complications. In the group with the lowest incidence of confirmed distal symmetric polyneuropathy (n = 123), confirmed distal symmetric polyneuropathy risk increased fivefold for those with the eNOS GG genotype (p < 0.05). In the group with the lowest risk of overt nephropathy (n = 340), the ACE D polymorphism increased overt nephropathy risk twofold (p = 0.05), whereas a protective effect was observed for the LIPC CC genotype (p < 0.05). In the group with the lowest incidence of coronary artery disease (n = 331), the MTHFR CC genotype increased coronary artery disease risk threefold (p < 0.05). Tree-structured survival analysis may help identify genetic predispositions among individuals who, despite low risk, develop diabetes-related complications.

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in Japan, Western Europe, and the United States. Mega studies such as Diabetes Control and Complication Trial (DCCT), Epidemiology of Diabetes Interventions and Complications (EDIC), and the United Kingdom Prospective Diabetes Study (UKPDS) clarified that poor glycemic and blood pressure control are undoubtedly involved in the development of nephropathy. However, these factors are not sufficient to predict which diabetic patients will develop renal disease, because not all patients with poor glycemic and blood pressure control develop renal disease. Since ethnic variations and familial clustering of diabetic nephropathy have been observed, genetic factors might contribute to susceptibility to this disease. Several methods such as (genome wide) association studies, sib-pair analysis, and quantitative trait loci (QTLs) analysis are available to examine polygenic diseases. However, no mutations that could explain the majority of nephropathy cases have been identified so far. The development of most diabetic nephropathy might be explained by the polygenic effect (i.e. many minor gene-gene interactions might be very important in the development of nephropathy). Identification of candidate genes of nephropathy enables targeting of therapy in patients at risk and development of novel therapeutic agents.

The ACE insertion/deletion polymorphism has been examined for association with diabetic nephropathy over the past decade with conflicting results. To clarify this situation, we conducted a comprehensive meta-analysis encompassing all relevant studies that were published between 1994 and 2004 and investigated this potential genetic association.

A total of 14,727 subjects from 47 studies was included in this meta-analysis. Cases (n=8,663) were type 1 or 2 diabetic subjects with incipient (microalbuminuria) or advanced diabetic nephropathy (proteinuria, chronic renal failure, end-stage renal disease). Control subjects (n=6,064) were predominantly normoalbuminuric.

No obvious publication bias was detected. Using a minimal-case definition based on incipient diabetic nephropathy, subjects with the II genotype had a 22% lower risk of diabetic nephropathy than carriers of the D allele (pooled odds ratio [OR]=0.78, 95% CI=0.69-0.88). While there was a reduced risk of diabetic nephropathy associated with the II genotype among Caucasians with either type 1 or type 2 diabetes, the association was most marked among type 2 diabetic Asians (Chinese, Japanese, Koreans) (OR=0.65, 95% CI=0. 51-0.83). This OR is significantly different from the OR of 0.90 (95% CI= 0.78-1.04) that was obtained for type 2 diabetic Caucasians (p=0.019). Using a stricter case definition based on advanced diabetic nephropathy, a comparable risk reduction of 24-32% was observed among the three subgroups, although statistical significance was reached only among Asians.

The results of our meta-analysis support a genetic association of the ACE Ins/Del polymorphism with diabetic nephropathy. These findings may have implications for the management of diabetic nephropathy using ACE inhibitors especially among type 2 diabetic Asians.

An imbalance in the hemostatic system is a frequent finding in untreated essential hypertension (HT), and it has been shown that treatment with angiotensin converting entyme (ACE) inhibitors improves hemostatic function. In order to elucidate the role of genetic factors, we studied hemostasis in patients with untreated and treated HT and correlated the results with ACE I/D and plasminogen activator enhibitor-1 (PAI-1) 4G/5G gene polymorphisms.

Forty-three males with HT (mean age 31.7 +/- 6.8 years) were compared with 34 age and gender-matched controls. All of the patients were treated with perindopril (4 mg/day) and, after one and six months of therapy, their levels of plasma fibrinogen (Fb), t-PA antigen, PAI-1 antigen, von Willebrand factor (vWF), ACE activity and blood pressure were measured. ACE and PAI-1 genotypes were identified by means of the polymerase chain reaction on DNA isolated from peripheral blood lymphocytes. Untreated patients had significantly higher levels of Fb, PAI-1 (p < 0.01) and t-PA (p < 0.05) regardless of their ACE or PAI-1 genotypes. Perindopril reduced blood pressure regardless of ACE or PAI-1 genotype (p < 0.001). ACE II homozygotes showed the greatest decrease in ACE activity (p < 0.01) and a significant reduction in Fb levels (p < 0.05) after just one month of treatment. Analysis of the group as a whole revealed an increase in t-PA antigen levels after six months of treatment, regardless of ACE or PAI-1 genotype (p < 0.01).

Our results show that essential hypertension predisposes to the procoagulant state characterized by hyperfibrinogenemia and hypofibrinolysis. Perindopril reduced fibrinogen levels in ACE II homozygotes due to its more potent inhibitory action on the renin-angiotensin system in such patients. It improved fibrinolysis by increasing t-PA levels regardless of ACE and PAI-1 genotype.

The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene might have consequences for the risks of vascular diseases. We examined the ACE genotype and the effects of a perindopril-based blood pressure-lowering regimen on macrovascular events, dementia, and cognitive decline among hypertensive and nonhypertensive patients with a history of cerebrovascular disease. ACE I/D genotypes were measured in 5688 of 6105 individuals with previous stroke or transient ischemic attack who participated in the PROGRESS trial. The DD genotype was significantly (P<0.0001) less frequent in Asian subjects (Chinese and Japanese, 14.7%) than in non-Asian subjects (32.0%). Controlling for racial background, there were no associations between ACE genotypes and cerebrovascular disease history or cardiovascular risk factors, including baseline blood pressure. The ACE genotype was not associated with the long-term risks of stroke, cardiac events, mortality, dementia, or cognitive decline; neither did the ACE genotype predict the blood pressure reduction associated with the use of the ACE inhibitor perindopril. Similarly, there was no evidence that the ACE genotype modified the relative benefits of ACE inhibitor-based therapy over placebo. This study provides no evidence that in patients with cerebrovascular disease, knowledge of ACE genotype is useful for predicting either the risk of disease or the benefits of perindopril-based blood pressure-lowering treatment.

Angiotensin converting enzyme (ACE) inhibitors preserve native kidney function in patients with renal disease better than other antihypertensive drugs, most likely because they more effectively reduce proteinuria. The plasma concentration of the ACE inhibitors target is, at least in part, under genetic control. A polymorphism of the ACE gene based on the presence or absence of a 287 base pair element in intron 16 accounts for 47% of the total phenotypic variance in the plasma ACE levels of healthy individuals. Unfortunately, pharmacogenetic studies performed so far do not provide a clear answer as to whether the efficacy of the reduction of proteinuria by ACE inhibitors is influenced by the ACE genotype - probably because these studies were not primarily designed to answer this question. This paper will try to outline some aspects that should be considered before an appropriate study on this topic is initiated.

To investigate the influence of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) gene variants on the response rate to therapy with the thiazolidinedione (TZD) pioglitazone, because in vitro studies have suggested that genetic variants of the PPAR-gamma gene may influence the drug efficacy of TZD.

A total of 131 patients were treated in an open-label, randomized, multicenter study with pioglitazone (45 mg o.d.) during a course of >or=26 weeks. Response to the pioglitazone therapy was defined by either a >20% decrease in fasting plasma glucose or a >15% decrease in HbA(1c) values after 26 weeks of pioglitazone treatment. We evaluated the association between the PPAR-gamma genotype and the response rate to pioglitazone treatment.

The Pro12Ala and the Pro12Pro variants in the PPAR-gamma gene are not associated with the response rate to pioglitazone treatment in patients with type 2 diabetes. However, we identified initial fasting plasma glucose level >11.0 mmol/l, HbA(1c) value >9.0%, BMI >32 kg/m(2), and fasting C-peptide concentrations at baseline >2.5 pmol/l as predominant confounding factors for the responder frequency to pioglitazone treatment.

The Pro12Ala variant in the PPAR-gamma gene does not affect the therapy efficacy of pioglitazone, suggesting that the drug-treatment response is independent from pharmacogenetic effects between PPAR-gamma and its ligand pioglitazone. Whether the Ala12Ala genotype plays a role in the response rate to TZD therapy remains to be determined.

Pharmacogenomics is a field aimed at understanding the genetic contribution to variability in drug efficacy and toxicity. The goal is to be able to select the drugs with the greatest likelihood of benefit and the least likelihood of harm in individual patients, based on their genetic make-up. Pharmacogenetics has historically been a field focused primarily on genetic polymorphisms in drug metabolizing enzymes and their impact on drug efficacy and toxicity. More recently, investigators have begun to study the relationship between drug target polymorphisms and drug efficacy and toxicity. There are now numerous examples in the literature of associations between drug target polymorphisms and drug effect. Drug targets can be broken into three main categories: the direct protein target of the drug, signal transduction cascades or downstream proteins, and disease pathogenesis proteins. While the drug target pharmacogenetics literature provides 'proof of concept' that genetic variability contributes to the variability in drug response, the data are not to the point of being clinically useful in most cases. Specific problems to date include the inability of a single polymorphism to be highly predictive of response, and inconsistencies across studies of the same polymorphism. It seems likely that an important factor in the above limitations is the approach of focusing on a single polymorphism in a single gene. Given that most drug responses involve a large number of proteins, all of whose genes could have several polymorphisms, it seems unlikely that a single polymorphism in a single gene would explain a high degree of drug response variability in a consistent fashion. Thus, it seems that a polygenic, or genomic approach will be more appropriate. Candidate gene and genome scanning approaches to pharmacogenomics have shown promise in relating drug target polymorphisms to response or toxicity, and pharmacogenomic strategies for drug discovery and drug development are now being implemented by most major pharmaceutical companies. Pharmacogenomics has the potential to significantly enhance the ability of clinicians to use medications in a safe and effective manner and, as such, represents an exciting field with tremendous clinical potential.

Perindopril erbumine (perindopril) is a prodrug ester of perindoprilat, an angiotensin converting enzyme (ACE) inhibitor. Perindopril 4 to 8 mg once daily significantly reduces supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline values in hypertensive patients. These reductions are maintained for at least 24 hours, as evidenced by trough/peak ratios of >50%. Vascular abnormalities associated with hypertension were improved or normalised during perindopril treatment. Perindopril 4 to 8 mg once daily significantly decreased carotid-femoral aortic pulse wave velocity (PWV), improved arterial compliance, reduced left ventricular mass index and, in patients with recent cerebral ischaemia and/or stroke, preserved cerebral blood flow despite significantly reducing SBP and DBP. Further research is needed to establish the significance of promising results showing that reductions in aortic PWV were associated with reduced mortality in patients with end-stage renal failure, a third of whom received perindopril. Response rates (numbers of patients with supine DBP < or = 90 mm Hg) were significantly higher with perindopril 4 to 8 mg once daily (67 to 80%) than with captopril 25 to 50 mg twice daily (44 to 57%) in 3 randomised double-blind trials. In other clinical trials, the antihypertensive effects of perindopril were similar to those of other ACE inhibitors (including enalapril) and calcium-channel antagonists. Combination treatment with perindopril and an antihypertensive agent from another treatment class provided additional benefits, either as first-line treatment or in patients failing to respond to monotherapy. Perindopril monotherapy was also effective in the elderly and in patients with hypertension and concomitant disease. Perindopril has a similar adverse event profile to that of other ACE inhibitors; cough is the most common event reported during treatment, and is also the most common adverse event responsible for treatment withdrawal.

Perindopril is a well tolerated ACE inhibitor that is significantly better than captopril (in terms of response rates) in the treatment of hypertension, and as effective as other ACE inhibitors. Perindopril appears to reverse some of the vascular abnormalities associated with hypertension, including arterial stiffness and left ventricular hypertrophy, although further research is needed to confirm promising results regarding its ability to decrease associated cardiovascular morbidity and mortality. Results from ongoing studies will help confirm the place of perindopril in the treatment of hypertension; currently, it is an effective and well tolerated treatment for patients with mild to moderate essential hypertension.