Genetic Variants of Angiotensin-Converting Enzyme Are Linked to Autism: A Case-Control Study

BackgroundAutism is a disease of complex nature with a significant genetic component. The importance of renin-angiotensin system (RAS) elements in cognition and behavior besides the interaction of angiotensin II (Ang II), the main product of angiotensin-converting enzyme (ACE), with neurotransmitters in CNS, especially dopamine, proposes the involvement of RAS in autism. Since the genetic architecture of autism has remained elusive, here we postulated that genetic variations in RAS are associated with autism.MethodsConsidering the relation between the three polymorphisms of ACE (I/D, rs4343 and rs4291) with the level of ACE activity, we have investigated this association with autism, in a case-control study. Genotype and allele frequencies of polymorphisms were determined in DNAs extracted from venous blood of 120 autistic patients and their age and sex-matched healthy controls, using polymerase chain reaction (PCR) and PCR–restriction fragment length polymorphism (PCR–RFLP) methods.ResultsThere were strong associations between both DD genotype of ACE I/D and the D allele, with autism (P = 0.006, OR = 2.9, 95% CI = 1.64–5.13 and P = 0.006, OR = 2.18, 95% CI = 1.37–3.48 respectively). Furthermore, a significant association between the G allele of rs4343 and autism was observed (P = 0.006, OR = 1.84, 95%CI = 1.26–2.67). Moreover, haplotype analysis revealed an association between DTG haplotype and autism (P = 0.008).ConclusionOur data suggests the involvement of RAS genetic diversity in increasing the risk of autism.     

Association of angiotensin-converting enzyme I/D polymorphism with heart failure: a meta-analysis

Heart failure (HF) is a complex clinical syndrome and is thought to have a genetic basis. Numerous case-control studies have investigated the association between heart failure and polymorphisms in candidate genes. Most studies focused on the angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism, however, the results were inconsistent because of small studies and heterogeneous samples. The objective was to assess the association between the ACE I/D polymorphism and HF. We performed a meta-analysis of all case-control studies that evaluated the association between ACE I/D polymorphism and HF in humans. Studies were identified in the PUBMED and EMBASE databases, reviews, and reference lists of relevant articles. Two reviewers independently assessed the studies. Seventeen case-control studies with a total of 5576 participants were included in the meta-analysis, including 2453 cases with HF and 3123 controls. The heterogeneity between studies was significant. No association was found under all the four genetic models (D vs. I, DD vs. ID and II, DD and ID vs. II, DD vs. ID). Subgroup analyses for ischemic HF (IHF) and HF because of dilated cardiomyopathy (DHF) also showed no significant association between ACE I/D polymorphism and HF. No significant association between the ACE I/D polymorphism and risk of HF was found in this meta-analysis. The future studies should focus on large-scale prospective and case-control studies which designed to investigate gene-gene and gene-environment interactions to shed light on the genetics of HF.     

Angiotensin-converting enzyme insertion/deletion polymorphism and risk of myocardial infarction in an updated meta-analysis based on 34 993 participants

The association between angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphism and risk of myocardial infarction (MI) has been extensively studied. However, the results were in controversy. This study aimed to explore the association between ACE I/D polymorphism and risk of MI by using a meta-analysis. We retrieved the following databases to indentify eligible studies: Medline, Embase, ISI, VIP, CBM and Wan Fang database. The latest update was 10th May, 2012. Odds ratio and 95% confidence interval (95% CI) were used to present the strength of the association. A total of 40 case–control studies with 34 993 participants were included. Overall, D allele of ACE I/D polymorphism was significantly associated with an increased risk of MI in genetic comparison models (OR (95% CI): 1.41 (1.22–1.64) for DD vs. II; 1.11 (1.01–1.21) for ID vs. II; 1.23 (1.10–1.37) for D carriers vs. II; 1.28 (1.15–1.43) for DD vs. I carriers and 1.06 (1.02–1.10) for D carriers vs. I carriers). Subgroup analyses, according to ethnicities and countries of participants also indicated that D allele was significantly associated with an increased risk of MI in Asians (especially for Chinese) and Caucasians (especially for English, French, Germans and Italians) (OR (95% CI) of DD vs. ID + II: 2.11 (1.65–2.70) for Asians and 1.15 (1.05–1.27) for Caucasians). In conclusion, this meta-analysis indicated that D allele of ACE I/D polymorphism was a possible risk factor for MI incidence for both Asians and Caucasians.     

Angiotensin-converting enzyme gene polymorphism is associated with anemia in non small-cell lung cancer

The angiotensin-converting enzyme (ACE) plays an important role not only in the regulation of vascular homeostasis but also in stimulation of hematopoiesis. We aimed to evaluate the association between insertion/deletion (I/D) polymorphism of the ACE gene and anemia at the time of the diagnosis. We enrolled 75 patients with non-small-cell lung cancer (NSCLC) and 85 age- and sex-matched healthy control participants. The I/D polymorphism of ACE was identified by using polymerase chain reaction from peripheral blood samples. Statistical analyses were performed with SPSS for Windows. The distributions of the ACE genotypes and alleles are similar in patients and in healthy participants (P=0.29 and P=0.08, respectively). In patients with NSCLC, 34 (45.3%) had anemia; of whom 3 (8.8%) had genotype II, 24 (70.6%) had genotype ID, and 7 (20.6%) had genotype DD (P=0.001). The patients with the II and ID genotypes had more frequent anemia at the time of the diagnosis (odds ratio = 6.02; P=0.001). Our findings suggest that I/D polymorphism of the ACE gene may influence the development of anemia in patients with NSCLC.     

Modification of the coronary artery disease risk associated with the presence of traditional risk factors by insertion/deletion polymorphism of the ACE gene

Cigarette smoking, hypercholesterolemia, and obesity influence the renin-angiotensin system (RAS) functions including an increased synthesis of the angiotensin I converting enzyme (ACE). Thus in the present work we explore the interactions of the ACE gene insertion/deletion (I/D) polymorphism and traditional risk factors. The study cohort included 341 subjects composed of 172 patients with angiographically confirmed CAD and 169 blood donors without a history of cardiovascular diseases. The I/D polymorphism was genotyped using polymerase chain reaction (PCR) methodology. To determine the interactions between the ACE genotypes and traditional risk factors the epidemiologic approach was used (4 x 2 tables and the synergy measures). The frequency of the DD genotype was significantly higher in patients than in controls (33.7% versus 21.3%, odds ratio [OR] = 1.88, 95% CI; 1.13-3.15, p = 0.010), but greater differences were found in males (35.7% versus 20.5%, OR = 2.15, 95% CI: 1.14-4.04, p = 0.010). We found a synergy of the DD genotype with smoking (SI = 1.88, SIM = 1.22), total cholesterol > or =5 mmol/l (SI = 2.12, SIM = 1.31) and elevated low density lipoprotein (LDL) cholesterol level (> or =3 mmol/l) (SI = 1.78, SIM = 1.14). The presence of the D allele (DD + ID subjects) also increased the risk of coronary artery disease (CAD) associated with the presence of elevated total cholesterol and LDL cholesterol (SI = 1.69, SIM = 1.18, in both cases), elevated level (> or =1.7 mmol/l) of triacylglycerols (SI = 1.81, SIM = 1.18) and overweight/obesity (SI = 4.25, SIM = 2.36). In each case the estimated CAD risk was greater than that predicted by assuming the additivity of effects (the risk increased from 69% for the D allele - total cholesterol interaction to 325% for the D allele - overweight/obesity). The statistical significance was also confirmed by a multiplicative model of synergy. The DD genotype/D allele of the ACE gene increases the risk of CAD associated with the presence of traditional risk factors.     

Genetic Associations of Angiotensin-Converting Enzyme with Primary Intracerebral Hemorrhage: A Meta-analysis

Background

A number of studies have reported an association of angiotensin-converting enzyme (ACE) gene polymorphism with primary intracerebral hemorrhage (PICH), however the reports have demonstrated inconclusive results. To clarify this conflict, we updated the previously performed meta-analysis by Peck et al., which revealed negative results, by investigating the ACE polymorphism and its correlation to PICH.

Methods

PubMed and Embase databases (through Dec 2012) were searched for English articles on the relationship of the I/D polymorphism in ACE with PICH in humans. Summary odds ratios (ORs) were estimated and potential sources of heterogeneity and bias were explored.

Results

A total of 805 PICH cases and 1641 control cases obtained from 8 case-control studies were included. The results suggest that in dominant genetic models, the ACE I/D polymorphic variant was associated with a 58% increase in susceptibility risk of PICH (OR = 1.58; 95% CI = 1.07–2.35 for DD vs. DI+II). However, in the subgroup analysis based on race, a significant increased risk was found in Asian DD homozygote carriers (OR = 1.76 and 95% CI = 1.16–2.66 for DD vs. DI+II), but not in Caucasian DD homozygote carriers (OR = 1.18, 95% CI = 0.36–3.88, P = 0.784 for DD vs. DI+II). The heterogeneity between studies was remarkable, and its major sources of heterogeneity were due to the year in which the study was published. No potential publication bias was observed in dominant genetic models.

Conclusions

These data demonstrated evidence of a positive association between ACE I/D polymorphism with PICH, and suggested that the ACE gene is a PICH susceptible gene in Asian populations.     

Association of angiotensin I-converting enzyme gene insertion/deletion polymorphism with rheumatic heart disease in Indian population and meta-analysis

Rheumatic heart disease (RHD) is one of the most severe consequences of rheumatic fever. It has been suggested that angiotensin I-converting enzyme (ACE) may be involved in the increased valvular fibrosis and calcification in the pathogenesis of RHD. We conducted a case–control study to look for association of ACE I/D polymorphism with RHD in Indian population. The study incorporated 300 patients (170 males and 130 females) with RHD, and 200 controls (118 males and 82 females). We also subgrouped RHD patients into mitral valve lesion (MVL) and combined valve lesion (CVL). ACE I/D polymorphism was identified using polymerase chain reaction method. We also performed a meta-analysis of three published studies and the present study (636 RHD cases and 533 controls) to evaluate the association between the ACE I/D polymorphisms and RHD risk. A significant difference in ACE ID and DD genotypes distribution between RHD cases (OR = 1.62, 95 % CI = 1.11–2.36 and OR = 2.08, 95 % CI = 1.02–4.15, respectively) and corresponding controls was observed. On comparing the ACE genotypes of MVL and CVL subgroups with controls, ID and DD genotypes were also significantly associated with CVL (FDR Pcorr = 0.009, OR = 2.19 and FDR Pcorr = 0.014, OR = 3.29, respectively). Meta-analysis also suggested association of the ACE D allele (FDR Pcorr = 0.036, OR—1.22, 95 % CI 1.02–1.45) with RHD. In conclusion, ACE ID and DD genotypes are associated with an increased risk of RHD, particularly CVL. This suggests that the ACE I/D gene polymorphism may play an important role in the pathogenesis of RHD.     

Lack of relationship between Alu repetitive elements in angiotensin converting enzyme and the severity of diabetic retinopathy

BackgroundAngiotensin-converting enzyme (ACE) stimulates angiogenesis that leads to the development of diabetic retinopathy (DR). Alu repetitive elements in ACE gene increase the expression of this enzyme. We investigated the frequency of Alu repetitive elements, insertion/deletion (I/D) polymorphism, in angiotensin-converting enzyme among diabetic retinopathy patients and whether this polymorphism is associated with the severity of retinopathy in Jordanians with type 2 diabetes.MethodsA total of 277 subjects participated in this case/ control study (100 diabetic patients without DR, 82 diabetic patients with DR, and 95 healthy control). Blood samples were withdrawn, followed by DNA extraction. Alu repetitive elements were examined by polymerase chain reaction followed by gel electrophoresis.ResultsThe genotype and allele frequencies among diabetic patients, were close to healthy controls (genotypes, II 44.4 vs. 44.7%, ID 44.4 vs. 42.6%, DD 12.2 vs. 12.8%, P = 0.402 and 0.677 respectively, alleles, I 65.6 vs. 66%, D 34.4 vs. 34%, P=0.863). Complicated diabetics with retinopathy showed similar genotype and allele frequency to those without complications. The severity of diabetic retinopathy in affected individuals was not correlated with I/D polymorphism (P=0.862).ConclusionsWe conclude that the presence of Alu repetitive elements did not increase the development or progression risk to retinopathy in Jordanian type 2 diabetic patients. No association between I or D alleles with the severity of DR was detected.     

飞行员中血管紧张素转换酶基因插入或缺失多态性研究

为了解飞行员血管紧张素转换酶(ACE)基因插入或缺失（I/D）多态性情况,探讨ACE基因多态性与飞行员耐力可能的关系,用聚合酶链反应（PCR）扩增技术检测118例飞行员和96例健康对照者的ACE基因I/D多态性。 结果位于ACE基因内含子16的I/D多态性经PCR扩增后呈三种基因型：纯合子插入型（II）、纯合子缺失型（DD）和杂合子插入或缺失型（I/D）。飞行员组II基因型（44.07%）和I等位基因频率（0.65）显著高于健康对照组(分别为31.25%和0.52)。 结果表明ACE I基因有可能在飞行员的飞行耐力中起重要作用。 Abstract:In order to understand insertion/delation (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in pilots,and to explore the relationship between ACE gene I/D polymorphism and the perfomance of the pilots,the polymerase chain reaction (PCR) was used to determine the genotypes for an I/D polymorphism in intron 16 of the ACE gene in 118 pilots and 96 healthy subjects as controls.The result showed that the I/D polymorphism in intron 16 of the ACE gene was categorized into three genotypes: two deletion alleles (genotype DD),heterozygous alleles (genotype ID),and two insertion alleles (genotype II).The genotype II and I allele frequency were significantly higher in pilots (44.07% and 0.65) than that in healthy subjects (31.25% and 0.52).It is suggested that I gene of ACE may play a role in perfomance of the pilots.     

The Influence of Angiotensin Converting Enzyme and Angiotensinogen Gene Polymorphisms on Hypertrophic Cardiomyopathy

Some studies have reported that angiotensin converting enzyme (ACE) and angiotensinogen (AGT) genes have been associated with hypertrophic cardiomyopathy (HCM). However, there have been inconsonant results among different studies. To clarify the influence of ACE and AGT on HCM, a systemic review and meta-analysis of case-control studies were performed. The following databases were searched to indentify related studies: PubMed database, the Embase database, the Cochrane Central Register of Controlled Trials database, China National Knowledge Information database, and Chinese Scientific and Technological Journal database. Search terms included “hypertrophic cardiomyopathy”, “angiotensin converting enzyme” (ACE) or “ACE” and “polymorphism or mutation”. For the association of AGT M235T polymorphism and HCM, “angiotensin converting enzyme” or “ACE” was replaced with “angiotensinogen”. A total of seventeen studies were included in our review. For the association of ACE I/D polymorphism and HCM, eleven literatures were included in the meta-analysis on association of penetrance and genotype. Similarly, six case-control studies were included in the meta-analysis for AGT M235T. For ACE I/D polymorphism, the comparison of DI/II genotype vs DD genotype was performed in the present meta-analysis. The OR was 0.73 (95% CI: 0.527, 0.998, P = 0.049, power = 94%, alpha = 0.05) after the study which deviated from Hardy-Weinberg Equilibrium was excluded, indicating that the ACE I/D gene polymorphism might be associated with HCM. The AGT M235T polymorphism did not significantly affect the risk of HCM. In addition, ACE I/D gene polymorphism did not significantly influence the interventricular septal thickness in HCM patients. In conclusion, the ACE I/D polymorphism might be associated with the risk of HCM.     

Association of angiotensin-converting enzyme (ACE) gene insertion–deletion polymorphism with spondylarthropathies

Summary Low back pain (LBP) is a common medical problem. Interaction between genetic and environmental factors predisposes individuals to LBP even at an early age. Inflammatory back pain or spondylarthropathies include ankylosing spondylitis (AS), psoriatic arthritis (PSA), reactive arthritis enteropathic and undifferentiated arthropathies. Angiotensin-converting enzyme (ACE) plays an important role in circulatory homeostasis, physiology of vasculature and inflammation. The insertion–deletion (I/D) polymorphism of the ACE gene has been shown to determine the plasma and tissue levels of ACE especially in the synovial fluid. The aim of this study was to investigate an association between ACE gene I/D polymorphism and inflammatory back pain (spondylarthropathies) secondary to ankylosing spondylitis (AS), psoriatic arthritis, inflammatory bowel disease and undifferentiated spondylarthropathies. The prevalence of ACE gene I/D polymorphism genotypes was determined in 63 patients with inflammatory back pain by polymerase chain reaction (PCR) and compared with that in 111 healthy controls. Of the 63 patients studied, 45 (71.4%) were with AS, 13 (20.6%) were with PSA, 4 (6.3%) were with reactive arthropathy and 1 (1.6%) manifested undifferentiated arthropathy. There were 43 males and 20 females. Mean age of patients was 39.0 ± 11.36 years, age at onset of spondylarthropathy was 27.7 ± 7.49 years and disease duration was 10.3 ± 7.74 months. The controls were selected to match with the patients group in terms of gender ratio, age and ethnicity. The ACE gene polymorphism showed an overall significant difference between patients and controls (p = 0.050). When the ID and II genotype frequency was combined and compared with that for DD genotype amongst patient and control groups, a considerably higher incidence was detected for ID and II genotypes than the DD genotype in spondylarthropathy patients compared to that in the controls (p = 0.036). This study showed a significant association of the I-allele of ACE gene I/D polymorphism with spondylarthropathy in Kuwaiti Arabs.     

Polymorphism of genes of the renin-angiotensin system ACE, AT1R, and AT2R in patients with pulmonary tuberculosis

The goal of this work was to verify the hypothesis about the possible role of some genes of the renin-angiotensin system in the innate immunity to tuberculosis. The insertion/deletion polymorphism (I/D) of the gene of the angiotensin-converting enzyme (ACE) is known to have an effect on the concentration of the angiotensin II in human body and also an indirect effect on various branches of metabolism. On the one hand, people with homozygote deletion of the ACE gene (DD genotype) are vulnerable to adiposity, arterial hypertension, hypercholesterolemia, and a number of other pathological conditions. On the other hand, it was shown that hypocholesterolemia is the general phenomenon for the patients with pulmonary tuberculosis (Perez-Guzman C. et al., Chest (2005)). In this work, we studied the I/D polymorphism of the gene ACE (genotypes DD, ID, and II), single nucleotide polymorphism (SNP) of the gene AT1R (1166 A/C), and SNP in 3123 positions of the gene AT2R (3123 A/C) in 200 patients with tuberculosis, 202 patients with essential hypertension, and 208 apparently healthy subjects. A group of patients with essential hypertension was used as a contrast group. According to the hypothesis stated above, the excess in the number of patients with the DD genotype (ACE) should be statistically significant in the group of patients with hypertension as compared to the group of patients with tuberculosis (chi2 = 9.64; chi2 = 0.0019; OR = 2.0; CI 1.2-3.3). There was a trend toward an increase in the rate of the DD genotype in the group of patients with tuberculosis relative to healthy subjects. Similar trend was observed in healthy subjects relative to the group of patients with hypertension. However, this difference was found to be statistically insignificant. The genotypes and allelotypes were compared in the group of patients with tuberculosis versus both the two control groups (healthy subjects and patients with hypertension). The significant difference from control was observed only in male rather than female patients with tuberculosis. It was shown that the greatest contribution to the distinction between groups was due to the genes ACE and AT2R. The combination of the genotypes of genes ACE and AT2R (ID+3123C) was met significantly more frequently in male patients with tuberculosis as compared to control group of healthy subjects (chi2 = 9.70; chi2 = 0.002; OR = 2.3; CI 1.2-4.3). The results obtained in this work are discussed in terms of the hypothesis stated above.     

Relationship of the angiotensin-converting enzyme gene polymorphism to glucose intolerance, insulin resistance, and hypertension in NIDDM

The deletion (D) allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been shown to be associated with cardiovascular and renal diseases in diabetes mellitus, but the mechanism underlying this association is not known. In addition, recent studies of the effect of the ACE gene on blood pressure have yielded conflicting results. Therefore, we studied the association of the ACE gene I/D polymorphism with glucose intolerance and insulin resistance, and the contribution of this locus to genetic susceptibility to hypertension in non-insulin-dependent diabetic mellitus (NIDDM). We analysed the ACE genotype in 84unrelated NIDDM patients with a known disease duration of less than 1year and in 115age- and sex-matched controls. The I/D polymorphism was determined by the polymerase chain reaction. There were no differences in ACE genotype distribution and allele frequencies between patients with NIDDM and nondiabetic controls. The frequencies of the D and Ialleles in both groups were identical, viz., 0.65 and 0.35, respectively. The NIDDM patients with the DD genotype had significantly higher blood glucose levels in the oral glucose tolerance test than those with the other genotypes; the incremental glucose area under the curve in the order of II, ID, and DD was 7.2 ± 2.4, 9.2 ± 4.0, and 10.7 ± 2.7mmol/l · h (II vs ID vs DD, P=0.0066 by ANOVA). No significant difference was found between the ACE genotype and serum insulin values. Similarly, there were no differences in body mass index, blood pressure, or serum lipids between the three genotypes. Among the nondiabetic controls, there was no statistically significant association of the I/D polymorphism with serum lipids, blood glucose levels, serum insulin concentrations, or blood pressure values. In conclusion, NIDDM patients with the DD genotype have higher blood glucose levels and are more glucose intolerant; this may help to explain the reported association between the Dallele and vascular complications in NIDDM. Received: 15 September 1997 / Accepted: 13 November 1997     

Association between Glu504Lys Polymorphism of ALDH2 Gene and Cancer Risk: A Meta-Analysis

BackgroundThe association of the aldehyde dehydrogenases-2 (ALDH2) Glu504Lys polymorphism (also named Glu487Lys, or rs671) and cancers has been investigated. This meta-analysis aims to comprehensively assess the influence of this polymorphism on the overall cancer risk.MethodsEligible publications were retrieved according to inclusion/exclusion criteria and the data were analyzed using the Review Manager software (V5.2).ResultsA meta-analysis based on 51 case-control studies consisting of 16774 cases and 32060 controls was performed to evaluate the association between the ALDH2 Glu504Lys polymorphism and cancer risk. The comparison of genotypes Lys+ (Lys/Lys and Lys/Glu) with Glu/Glu yielded a significant 20% increased cancer risk (OR = 1.20, 95%CI: 1.03–1.39, P = 0.02, I² = 92%). Subgroup analysis by cancer type indicated a significantly increased UADT cancer risk (OR = 1.39, 95%CI: 1.11–1.73, P = 0.004, I² = 94%) in individuals with the Lys+ genotypes. Subgroup analysis by country indicated that individuals from Japan with the Lys+ genotypes had a significant 38% increased cancer risk (OR = 1.38, 95%CI: 1.12–1.71, P = 0.003, I² = 93%).ConclusionsOur results indicated that the ALDH2 Glu504Lys polymorphism is a susceptible loci associated with overall cancers, especially esophageal cancer and among Japanese population.     

在中国北方汉族人群中血管紧张素转换酶基因I/D多态与G蛋白beta3亚基基因C825T多态对原发性高血压的联合作用

原发性高血压是一种复杂的多基因疾病,被认为是多个变异了的基因遗传交互以及环境因素共同作用的结果.证据表明,血管紧张素转换酶基因和G蛋白beta3亚基基因各自都是重要的原发性高血压的易感基因,并且可能存在共同的通路来导致高血压疾病的发展.为了探索这两个基因在中国北方汉族人群中是否对高血压有影响,挑选血管紧张素转换酶基因I/D多态与G蛋白beta3亚基基因C825T多态,在一个包含502个高血压病例和490个健康对照的样本中做了关联研究.连锁不平衡分析揭示,仅仅在男性中有显著性的非随机性分布,表明血管紧张素转换酶基因与G蛋白beta3亚基基因倾向在男性中造成高血压.调整了的单位点的多变量逐步回归分析展示,在男性显性模型中DD/ID对Ⅱ的比值比达到显著性水平(OR1.57;95%CI,1.09～2.27;P=0.016).在对性别进行分层后的联合分析中,在男性中经过调整后的比值比具有弱显著性水平:在血管紧张素转换酶基因的DD基因型中,TT对CC的比值比是0.11;95%CI,0.01～0.99;P=0.049;在G蛋白beta3亚基基因的CC CT基因型中,DD/ID对Ⅱ的比值比是1.52;95%CI,1.01～2.29;P=0.047.结果暗示,血管紧张素转换酶基因或附近的某个基因是具有男性性别倾向的高血压易感侯选基因,同时,在血管紧张素转换酶基因基因的D等位基因和G蛋白beta3亚基基因的825C等位基因之间,可能存在具有上位效应的基因-基因相互作用.     

The frequency of factor V Leiden mutation,ACE gene polymorphism,serum ACE activity and response to ACE inhibitor and angiotensin II receptor antagonist drugs in Iranians type II diabetic patients with microalbuminuria

The aim of present study was to determine if factor V Leiden (FVL) mutation and angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism are associated with diabetic nephropathy (DN) among Kurdish population from Western Iran. This case–control study comprised 144 unrelated adult type 2 diabetic mellitus patients (T2DM) including 72 patients with microalbuminuria and 72 age and sex matched patients without nephropathy. The ACE I/D polymorphism and FVL mutation were detected by polymerase chain reaction (PCR) and PCR–RFLP, respectively. The frequency of FVL G1691A and ACE D allele in T2DM patients with microalbuminuria were 1.6 and 57%, respectively and in normoalbuminuric T2DM patients were 4.9 and 58.3%, respectively (P > 0.05). ACE genotypes affected on serum ACE activity and a better response to ACE inhibitor therapy (captopril) compared to angiotensin II receptor antagonist (losartan) was obtained with significant reduction of ACE activity in diabetic patients without nephropathy carrying DD genotype. However, the beneficial effect of losartan therapy was observed in microalbuminuric patients with II genotype compared to ID and DD genotypes.     

Association of angiotensin-converting enzyme and endothelial Nitric Oxide synthase gene polymorphisms with vascular disease in ESRD patients in a Chinese population

Background The effect of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and endothelial Nitric Oxide synthase (eNOS) gene G894 → T on vascular disease in end-stage renal disease (ESRD) patients was rarely studied previously. We investigated such effect in a Chinese population. Methods A total of 153 ESRD patients with vascular disease (88 men and 65 women; mean age ± SD: 54.0 ± 13.2) were recruited. Polymerase chain reaction was used to classify the ACE genotypes as II, ID and DD and the eNOS genotypes as GG, GT, and TT. Analyses were performed in ESRD patients with vascular disease (n = 153) and the age-matched controls (n = 148). Results The frequencies of ACE DD and eNOS TT genotypes and ACE D and eNOS T alleles in ESRD patients with vascular disease were significantly higher than those in the controls (P < 0.05). There was a significant interaction between ACE I/D alleles and eNOS G894 → T polymorphism: adjusted odds ratio 2.128 (95%CI 1.022–4.434, P = 0.017). Conclusions These results indicated that the etiology of vascular disease in ESRD patients is associated with ACE and eNOS (G894 → T) gene polymorphisms. Our data also suggest that an interaction effect may exist between ACE (I/D) and eNOS (G894 → T) polymorphism in increasing the risk of vascular complications in ESRD patients     

Interactions among Candidate Genes Selected by Meta-Analyses Resulting in Higher Risk of Ischemic Stroke in a Chinese Population

Ischemic stroke (IS) is a multifactorial disorder caused by both genetic and environmental factors. The combined effects of multiple susceptibility genes might result in a higher risk for IS than a single gene. Therefore, we investigated whether interactions among multiple susceptibility genes were associated with an increased risk of IS by evaluating gene polymorphisms identified in previous meta-analyses, including methylenetetrahydrofolate reductase (MTHFR) C677T, beta fibrinogen (FGB, β-FG) A455G and T148C, apolipoprotein E (APOE) ε2–4, angiotensin-converting enzyme (ACE) insertion/deletion (I/D), and endothelial nitric oxide synthase (eNOS) G894T. In order to examine these interactions, 712 patients with IS and 774 controls in a Chinese Han population were genotyped using the SNaPshot method, and multifactor dimensionality reduction analysis was used to detect potential interactions among the candidate genes. The results of this study found that ACE I/D and β-FG T148C were significant synergistic contributors to IS. In particular, the ACE DD + β-FG 148CC, ACE DD + β-FG 148CT, and ACE ID + β-FG 148CC genotype combinations resulted in higher risk of IS. After adjusting for potential confounding IS risk factors (age, gender, family history of IS, hypertension history and history of diabetes mellitus) using a logistic analysis, a significant correlation between the genotype combinations and IS patients persisted (overall stroke: adjusted odds ratio [OR] = 1.57, 95% confidence interval [CI]: 1.22–2.02, P < 0.001, large artery atherosclerosis subtype: adjusted OR = 1.50, 95% CI: 1.08–2.07, P = 0.016, small-artery occlusion subtype: adjusted OR = 2.04, 95% CI: 1.43–2.91, P < 0.001). The results of this study indicate that the ACE I/D and β-FG T148C combination may result in significantly higher risk of IS in this Chinese population.     

Insertion/deletion polymorphism of the angiotensin converting enzyme gene in coronary artery disease in southern Turkey

Genetic factors are important in the pathogenesis of coronary artery disease (CAD). Angiotensin converting enzyme (ACE) gene insertion(I)/deletion(D) polymorphism is one of the genetic factor found to be related with CAD. We investigated the association between I/D polymorphism of the ACE gene and the presence of CAD. Three hundred and seven patients (187 males and 120 females, aged between 35-80, mean 54.3 +/-9.8 years) who underwent diagnostic coronary angiography were included in the study. ACE I/D polymorphism was detected by polymerase chain reaction. Of the 307, 176 had CAD. The most frequently observed genotype in all subjects was ID (47.9 %). However, in patients with CAD the frequency of II genotype was lower whereas DD genotype was higher compared to the controls (p < 0.05). The number of D allele carrying subjects were also higher (p < 0.05) in CAD patients. The logistic regression analysis indicated that the ACE D allele is an independent risk factor (odds ratio = 1.48, 95 % CI = 1.01-2.18, p < 0.05). In conclusion, the I/D polymorphism of ACE gene (carrying D allele) is an independent risk factor for CAD in the studied Turkish population.