Angiotensin-converting enzyme insertion/deletion polymorphism and systemic lupus erythematosus: a metaanalysis

OBJECTIVE: To explore whether insertion (I) and deletion (D) polymorphisms within intron 16 of the angiotensin-converting enzyme (ACE) gene confer susceptibility to systemic lupus erythematosus (SLE) and lupus nephritis (LN). METHODS: We surveyed studies of ACE I/D polymorphism and SLE using Medline and manual searches. We conducted a metaanalysis of the DD genotype (recessive effect), DD and DI genotype (dominant effect), and D allele of the ACE overall and in each ethnic population. We performed a metaanalysis of ACE I/D polymorphism in SLE and LN. RESULTS: Thirteen comparison studies were included in our metaanalysis consisting of 1411 patients with SLE and 1551 controls. We found no association of ACE I/D polymorphism with SLE in the total sample and by ethnic groups. There was a trend for association of the DD genotype (OR 1.212, 95% CI 0.966-1.520, p = 0.097) and the D allele with SLE in Caucasian patients (OR 1.157, 95% CI 0.991-1.349, p = 0.064); however, this was not statistically significant. The metaanalysis also showed no association of the ACE I/D polymorphisms with LN. CONCLUSION: This metaanalysis of 2962 subjects showed there is a lack of association of the ACE I/D polymorphism with SLE and LN.     

Sex difference in the effect of ACE-DD genotype on the risk of premature myocardial infarction

In this association study the authors compared the insertion/deletion (I/D) angiotensin-I converting enzyme (ACE) gene polymorphism in females and males with premature myocardial infarction (MI). I/D ACE gene polymorphism was tested in 738 subjects: 302 patients with MI (151 men and 151 women) and 436 healthy subjects (207 men and 229 women). In women the ACE-DD genotype was not associated with MI (OR 1.1, 95% CI 0.6-2.1, p=0.6), whereas the ACE-DD genotype conferred a 2-fold independent risk for MI in men (95% CI=1.2-3.4; p=0.013) after adjustment for cardiovascular risk factors. The authors found evidence for the sex difference in the effect of the ACE-DD genotype on MI risk. The ACE-DD genotype conferred a 2-fold independent risk for premature MI in males.     

Angiotensin-converting enzyme (ACE) genotypes and disability in hospitalized older patients

The association between angiotensin-converting enzyme (ACE) genotypes and functional decline in older adults remains controversial. To assess if ACE gene variations influences functional abilities at older age, the present study explored the association between the common ACE insertion/deletion (I/D) polymorphism and disability measured with activities of daily living (ADL) in hospitalized older patients. We analyzed the frequency of the ACE genotypes (I/I, I/D, and D/D) in a population of 2,128 hospitalized older patients divided according to presence or absence of ADL disability. Logistic regression analysis adjusted for possible confounding factors, identified an association between the I/I genotype with ADL disability (OR=1.54, 95% CI 1.04-2.29). This association was significant in men (OR=2.01, 95% CI 1.07-3.78), but not in women (OR=1.36, 95% CI 0.82-2.25). These results suggested a possible role of the ACE polymorphism as a genetic marker for ADL disability in hospitalized older patients.     

Multiple Polymorphisms in the renin- angiotensin-aldosterone system (ACE, CYP11B2, AGTR1) and their contribution to hypertension in African Americans and Latinos in the multiethnic cohort

OBJECTIVE: When compared with other U.S. populations, African Americans have excess hypertension. Genetic variants in elements of the renin-angiotensin-aldosterone system (RAAS), namely the angiotensin-converting enzyme (ACE), aldosterone synthase (CYP11B2), and angiotensin II type 1 receptor (AGTR1) genes, have been associated with risk of hypertension in some populations. METHODS: We genotyped the D/I polymorphism in the ACE gene, the C(-344)T polymorphism in the CYP11B2 gene, and the C(-535)T polymorphism in the AGTR1 gene among African American and Latino members of the Multiethnic Cohort Study (MEC) to determine their association with hypertension. RESULTS: We observed no significant increase in the risk of hypertension for either African Americans or Latinos homozygous or heterozygous for the D allele of the ACE gene. Among African Americans we observed carriers of the (-344)T allele of CYP11B2 to be at increased risk of hypertension (versus CC genotype: TC genotype, OR = 1.66 [95% CI: 1.01-2.72]; TT genotype, OR = 1.74 [95% CI: 1.07-2.82]). There was also an increase in risk of hypertension associated with the AGTR1 T allele for African Americans (versus CC genotype: TC genotype, OR = 2.62 [95% CI: 1.46-4.72]; TT genotype, OR = 2.67 [95% CI: 1.51-4.74]). The associations observed with CYP11B2 and AGTR1 genotypes were not observed among Latinos. CONCLUSION: These data suggest that the (-535)T allele of AGTR1 and (-344)T allele of CYP11B2 may increase hypertension risk among African Americans but not among Latinos. Characterization of the linkage disequilibrium and haplotype patterns in the RAAS pathway genes will be crucial to understanding differences in hypertension susceptibility in these ethnic populations.     

Analysis of the postulated interaction between the angiotensin II sub-type 1 receptor gene A1166C polymorphism and the insertion/deletion polymorphism of the angiotensin converting enzyme gene on risk of myocardial infarction

A synergistic interaction between the insertion/deletion (I/D) polymorphism within the angiotensin-converting enzyme (ACE) gene and an A/C transversion at nucleotide position 1166 within the angiotensin II sub-type 1 receptor (AT1R) gene on risk of myocardial infarction has been reported. The risk associated with the ACE DD genotype increased with the number of AT1R C alleles present. To investigate this further, ACE I/D and AT1R A1166C genotypes were determined in 541 cases recruited at the time of infarction and 507 population-based controls. There was no difference in either the genotype distribution or allele frequencies between cases and controls for either the ACE polymorphism (P=0.48 and 0.35 respectively) or the AT1R polymorphism (P=0.35 and 0.21 respectively). Odds ratios for risk of MI associated with the ACE DD and AT1R CC genotypes were 1.09 (95% CI, 0.82-1.45) and 1.06 (0.67-1.68) respectively. 3.1% of cases versus 3.6% of controls were homozygous for both the D and C alleles (P=0.71). There was no increase in risk associated with the DD genotype in the presence of either one or two AT1R C alleles in the whole cohorts (OR 0.99, 95% CI 0.65-1.51 and 0.76, 95% CI 0.30-1.88, respectively) nor in sub-groups defined by specific risk factors. In conclusion, no evidence was found to support any interaction between the ACE gene I/D polymorphism and the ATIR gene A1166C transversion in determining the risk of myocardial infarction in the population studied.     

The involvement of the renin-angiotensin system gene polymorphisms in coronary heart disease

INTRODUCTION AND OBJECTIVES: Previous studies angiotensin-converting enzyme gene insertion/deletion polymorphism ACE (I/D), angiotensinogen gene polymorphism, and angiotensin II AT1 receptor polymorphism in relation to coronary heart disease controversial results. This study was designed to analyze the association between these gene polymorphisms and the first coronary event in individuals residing on Grand Canary Island, Spain. PATIENTS AND METHOD: Case-control study. Case subjects (n = 304) were recruited at the first coronary event; age-matched controls (n = 315) were randomly selected from the Grand Canary population. Participants were examined for the usual risk factors. Blood samples were obtained for biochemical analyses and DNA extraction. Genotyping was performed by PCR and restriction analysis. RESULTS: Neither ACE (I/D) nor AT1 receptor polymorphism was associated with coronary heart disease, whereas the frequency distribution of AGT M235T genotypes among patients and control subjects (TT: 29% and 19%; MT: 48% and 50%; MM: 22% and 31%, respectively) was statistically different (p = 0.003). Multiple logistic regression analysis identified the TT genotype of the angiotensinogen gene (OR = 1.9; 95% CI 1.1-3.4), diabetes (OR = 4.4; 95% CI 2.0-9.4) and hypertension (OR = 2.1; 95% CI 1.3-3.3) as risk factors predicting the coronary event. CONCLUSIONS: Our results provide no evidence of an association between ACE (I/D) or AT1 receptor polymorphism and coronary heart disease. However, homozygosity for the T allele of the angiotensinogen gene, diabetes and hypertension independently place individuals at higher risk of experiencing a coronary event on Grand Canary Island.     

Relation between the insertion/deletion polymorphism of the angiotensin I converting enzyme gene and restenosis after coronary stenting

BACKGROUND: Observations with intravascular ultrasound demonstrated that neointimal hyperplasia is the predominant factor responsible for in-stent restenosis. Experimental data suggest that angiotensin I converting enzyme (ACE) plays a role in the thickening of neointima after balloon denudation. Insertion/deletion (I/D) polymorphism of the ACE gene is significantly associated with plasma level of ACE and subjects with D/D genotype have significantly higher plasma levels of ACE than normal. OBJECTIVE: To investigate whether this polymorphism influences the risk of restenosis after coronary stenting. METHODS: We genotyped 158 patients who had undergone single-vessel coronary stenting for the ACE I/D polymorphism. RESULTS: Of the 158 patients, 56 (35%) had the D/D genotype, 71 (45%) had the I/D genotype and 31 (20%) had the I/I genotype. Prevalences of genotypes were compatible with Hardy-Weinberg equilibrium and distributions of ACE genotype among patients and 132 healthy controls from the same geographic area did not differ. At follow-up (after a median duration of 5.4 months), overall rates of angiographic restenosis and of revascularization of target lesion (RTL) were 32.3 and 22.8%, respectively. Of 51 patients with angiographic restenosis, 31 (60.8%) had focal and 20 (39.2%) had diffuse patterns of restenosis. Diffuse in-stent restenosis was significantly more prevalent among patients with D/D genotype (P = 0.016). Multiple stepwise logistic regression analysis identified ACE I/D polymorphism as the independent predictor of angiographic restenosis and RTL. Relative risk of angiographic restenosis was 6.29 [95% confidence interval (CI), 1.80-22.05, P = 0.0004] for D/D genotype and 3.88 (95% CI 1.11-13.12, P = 0.029) for I/D genotype, whereas relative risk of RTL was 7.44 (95% CI 1.60-34.58, P = 0.01) for D/D genotype and 3.88 (95% CI 0.083-18.15, P = 0.085) for I/D genotype. CONCLUSIONS: The ACE I/D polymorphism is significantly associated with risk of angiographic and clinical restenosis after coronary stenting. Angiographic pattern of restenosis is also significantly associated with I/D polymorphism, diffuse type being more prevalent among subjects with D/D genotype.     

Association between angiotensin I-converting enzyme gene insertion/deletion polymorphism and risk of rheumatic heart disease

Scarring and collagen deposition in the valves and destruction of myocytes may result from the combined effects of a smoldering rheumatic process and a constant trauma to the mitral valve or aortic valve by the turbulent flow in rheumatic heart disease (RHD). It has been suggested that angiotensin I-converting enzyme (ACE) may be responsible for the increased valvular fibrosis and calcification in the pathogenesis of RHD. However, the role of ACE genetic variant in RHD has not been studied among the Chinese population in Taiwan. Hence, a case-controlled study was carried out to investigate the possible relationship between the ACE gene insertion/deletion (I/D) and G2350A polymorphisms and RHD. A group of 115 patients with RHD documented by echocardiography and 100 age- and sex-matched normal control subjects were studied. ACE gene I/D and G2350A polymorphisms were identified by polymerase chain reaction-based restriction analysis. There was a significant difference in the distribution of ACE I/D genotypes (P = 0.02) and allelic frequencies (P = 0.04) between RHD cases and normal controls. An odds ratio for the risk of RHD associated with the ACE I/D II genotype was 2.12 (95% CI, 1.21-3.71). An odds ratio for the risk of RHD associated with the ACE I allele was 1.50 (95% CI, 1.02-2.21). The ACE G2350A polymorphism showed no association with RHD (P = 0.90). Further categorization of RHD patients into mitral valve disease and combined valve disease subgroups revealed no statistical difference in these gene polymorphisms when compared between the two subgroups. This study shows that patients with RHD have a higher frequency of ACE II genotype and I allele, which supports a role for ACE I/D gene polymorphisms in determining the risk of RHD in Taiwan Chinese.     

血管紧张素转换酶和血管紧张素Ⅱ受体1A1166C基因多态性与脑出血的关系

目的探讨血管紧张素转换酶（ACE）基因插入/缺失多态性和血管紧张素Ⅱ受体1（AT1R）A1166C基因多态性与脑出血的关系,并分析两者是否有协同致脑出血的效应。方法应用聚合酶链反应及限制性片段长度多态性技术,检测80例脑出血患者（脑出血组）和90名健康对照者（健康对照组）的ACE和AT1R基因型和等位基因,并运用Logistic回归分析不同基因型致脑出血的效应。结果脑出血组ACEDD基因型频率为35.0%,D等位基因频率为51.9%,明显高于健康对照组的15.6%和38.9%,均P〈0.05;AT1RAC基因型频率为32.5%,C等位基因频率为16.2%,明显高于健康对照组的11.1%和5.6%,均P〈0.05;Logistic回归显示,170例入组者中,携带AT1RAC基因型（OR：3.852,95%CI：1.719～8.632;P〈0.01）、ACE基因DD型（OR：2.923;95%CI：1.406～6.079;P〈0.01）及同时携带有AT1RAC基因型和ACEDD基因型（OR：4.250;95%CI：1.479～12.209;P〈0.01）是脑出血的独立危险因素。结论ACE基因插入/缺失多态性和AT1RA1166C基因多态性可能是脑出血发病的独立遗传因素;且两者间具有协同致脑出血的作用。     

血管紧张素转换酶基因插燃失多态性与中国汉族人群心肌梗死相关洼的Meta分析

目的采用Meta分析的方法探讨血管紧张素转换酶基因插入/缺失（ACEI/D）多态性与中国汉族人群心肌梗死（MI）的相关性。方法系统检索中国生物医学文献数据、中国期刊全文数据库、中文科技期刊全文数据库和万方数据库中1995年至2012年6月间公开发表的病例-对照研究,对符合纳入标准的研究进行数据提取后采用Meta-Analyst3软件进行Meta分析,采用漏斗图检验发表偏倚。结果共纳入24项病例-对照研究,1821例MI患者和1951例对照。总体人群和亚组Meta分析结果均表明ACEI/D多态性与中国汉族人群MI相关性密切相关,携带D等位基因能够显著增加MI的易感性[Ivs.D：OR=0.56,95%CI：0.49～0.64;IIvs.DD：OR=0.37,95%CI：0.29～0.46;IDvs.DD：OR=0.48,95%CI：0.39～0.59;（ID＋II）vs.DD：OR=0.43,95%CI：0.34～0.53;IIvs.（DD＋ID）：OR=0.57,95%CI：0.50～0.66]。有轻微的发表偏倚存在。结论本研究结果支持ACEI/D多态性与中国汉族人群MI发病风险相关,但并不能证明I/D多态性是MI的独立危险因素,亦不能证明D等位基因为致病基因、I等位基因为保护基因。     

血管紧张素转换酶基因变异与上海地区汉族人群原发性高血压易感性相关

目的原发性高血压是一种多基因病,受遗传及多种环境因素的影响。肾素一血管紧张素．醛固酮系统（RAAS）在调节盐代谢、血压的调控及高血压的发病中起着重要作用。本研究旨在探讨血管紧张素转换酶（ACE）基因插入／缺失（insertion／deletion,I／D）变异与中国上海地区汉族人群原发性高血压的关系。对象与方法选择上海地区无血缘关系的原发性高血压患者（EH）200例及血压正常的对照个体（NT）185例。盐析法提取外周血白细胞中的基因组DNA。应用聚合酶链式反应（PCR）、三条引物法对ACE基因I／D变异进行基因型鉴定。结果EH组与NT组基因型分布符合Hardy．Weinberg平衡。分别采用显性模型（ID＋DDvs．Ⅱ）及加性模型（DDvs．IDvs．Ⅱ）分析基因型分布在病例组与对照组之间的差异。用Logistic回归模型校正了年龄、性别及体重指数后,ACED等位基因携带者与Ⅰ等位基因携带者相比,原发性高血压易感性增加（显性模式：OR=2．27,95％可信限1．41-3．65,P=0．001;加性模式：OR=2．02,95％可信限1．38-2．96,P=0003）。结论ACE基因I／D变异与上海地区汉族人群原发性高血压的易感性相关。     

Interaction of the ACE D allele and the GNB3 825T allele in myocardial infarction

In polygenetic disorders, such as ischemic heart disease, the investigation of gene-gene interactions rather than determination of single gene effects is crucial to better understand the contribution of genetic factors. The 825T allele of the G-protein ss(3)-subunit gene (GNB3) associated with enhanced G-protein signaling is a candidate to interact with the angiotensin-converting enzyme (ACE) deletion/insertion (D/I) polymorphism to increase the risk for myocardial infarction (MI). The ACE D:/I variant affects the renin-angiotensin system hormones that activate G-protein-coupled receptors. Genotyping at the ACE and GNB3 loci was performed on 585 patients with coronary artery disease with (n=270) or without (n=315) previous MI. Logistic regression analysis demonstrated a significant interaction between the ACE D: allele and the GNB3 825T allele (P<0.001). The odds ratio for MI, associated with the 825T allele, was not increased in the presence of the ACE II genotype (OR 0.5; P=0.09) but was significantly higher in 825T allele carriers with the ACE DI genotype (OR 1.9; P=0.01) and further increased in individuals with the ACE DD genotype (OR 2.4; P=0.02). The highest odds ratio was found in homozygous 825T allele carriers with the ACE DD genotype (OR 7.5; P=0.006). Our data suggest a significant interaction of the GNB3 825T allele with the ACE D allele in MI. These hypothesis-generating data may justify larger prospective studies.     

Angiotensin-converting enzyme gene polymorphism in north Indian population with obstructive sleep apnea

Background

A deletion of 287-bp Alu repeat of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene is associated with hypertension.

Purpose

The aim of this study is to determine the frequency of ACE (I/D) polymorphism in patients with obstructive sleep apnea (OSA).

Methods

Genotyping of ACE (I/D) gene polymorphism and estimation of serum angiotensin-converting enzyme (SACE) activity were done in 813 subjects who underwent polysomnography. Of these, 395 were apneics and 418 were non-apneics.

Results

The frequencies of II genotype (OR = 1.8, 95 % CI 1.26–2.60, p?=?0.001) and I allele (OR = 1.4, 95 % CI 1.13–1.69, p?=?0.001) of ACE gene were found to be significantly increased in patients with OSA as compared to patients without OSA. Frequency of II genotype was significantly decreased (OR = 0.46, 95 % CI 0.28–0.77, p?=?0.003) in OSA patients with hypertension. In contrast, the frequencies of ID (OR?=?1.80, 95 % CI 1.08–2.99, p?=?0.024) and DD genotypes (OR?=?2.15, 95 % CI 1.30–3.57, p?=?0.003) were significantly increased in this group. The activity of SACE was significantly decreased in the apneic group as compared to the non-apneic group (OR?=?0.99, 95 % CI 0.98–1.00, p?=?0.04).

Conclusions

The findings suggest that II genotype confers susceptibility towards development of OSA whereas DD genotype confers susceptibility towards hypertension irrespective of OSA.     

Genetic variation in the renin-angiotensin system modifies the beneficial effects of ACE inhibitors on the risk of diabetes mellitus among hypertensives

The aim of this study was to assess whether the association between angiotensin-converting enzyme (ACE) inhibitor use and the incidence of treated diabetes mellitus is modified by genetic polymorphisms in the renin-angiotensin system (RAS).In a nested case-control study, treated hypertensive patients were genotyped for ACE (insertion (I)/deletion (D)), angiotensinogen (AGT; M235T) and angiotensin II type 1 receptor (AGTR1; A1166C). Cases of newly treated diabetes were identified based on pharmacy records and controls were not yet drug treated for diabetes (case:control ratio 1:10). Self-administered questionnaires and physical examinations were used to assess risk factors for diabetes mellitus. Logistic regression was used to calculate the relative risk of diabetes associated with ACE inhibitor use relative to other antihypertensive treatment, stratified by the RAS genotypes. Among 205 cases and 2050 controls, homozygous 1166A carriers of the AGTR1 gene had a significantly decreased incidence of diabetes associated with current use of ACE inhibitors (odds ratio, OR: 0.47; 95% CI: 0.26-0.84), whereas this incidence was increased among 1166C allele carriers (OR: 1.32; 95% CI: 0.81-2.14). The interaction OR was 3.21 (95% CI: 1.53-6.75). ACE I allele carriers had a significantly reduced incidence of diabetes associated with ACE inhibitors use (OR: 0.63; 95% CI: 0.41-0.98), whereas DD homozygotes had no reduced risk (OR: 0.95; 95% CI: 0.46-1.96). The risk of diabetes associated with ACE inhibitor use was not significantly modified by the AGT-M235T polymorphism. Treatment with ACE inhibitors in hypertensive subjects significantly reduces the occurrence of diabetes in homozygous 1166A carriers of the AGTR1 gene and carriers of the ACE I allele, but not in 1166C allele carriers of the AGTR1 gene and in homozygous ACE D allele carriers.     

Angiotensin-converting enzyme gene polymorphism and vascular manifestations in Korean patients with SLE

Systemic lupus erythematosus (SLE) is an inflammatory multisystem disease of unknown etiology with immunologic aberrations. Many studies have shown that genetic and environmental factors are implicated in the development of SLE. Angiotensin-converting enzyme (ACE) affects various immune phenomena through the renin-angiotensin and kallikrein-kininogen systems by creating angiotensin II and inactivating bradykinin. We investigated the correlation between insertion/ deletion polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement and lupus nephritis. Two-hundred and eleven Korean patients fulfilling the ACR criteria and 114 healthy subjects were enrolled. The ACE genotype was determined by polymerase chain reaction using genomic DNA from peripheral blood. The nephritis patients were classified by the WHO classification. In addition, the activity and chronicity index were used to assess the severity of renal involvement. We evaluated vascular involvement by the presence or absence of hypertension, Raynaud's phenomenon, livedo reticularis, antineutrophil cytoplasmic antibody and the SLICC/ACR Damage Index. The gene frequency of ACE gene polymorphism was as follows: II 39 vs 34%, ID 41 vs 50%, DD 20 vs 16% in SLE patients and controls, respectively. There was no difference in genotype frequency between both groups. There were no significant differences between the distribution of ACE gene genotypes and lupus nephritis and its related parameters, including WHO classification, activity index, chronicity index, renal dysfunction and amount of 24 h urinary protein. The ACE genotypes and alleles did not affect the presence of vascular manifestations evaluated, but the frequency of DD genotype was significantly low in SLE patients with Raynaud's phenomenon compared to those without Raynaud's phenomenon (P = 0.002 for ACE ID vs DD and II, OR 2.7, 95% CI 1.43-5.09; P=0.023 for ACE DD vs ID and II, OR 0.33, 95% CI 0.12-0.89). Also skewing from DD to II genotype was noted in patients with anti-Sm antibody compared to those without anti-Sm antibody (P = 0.025 for ACE DD vs ID and II, OR 0.21, 95% CI 0.05-0.93). The onset age of serositis was older in patients with the ID genotype than the others (ID= 34.5+/-10.8, II + DD = 25.6+/-10.2, P= 0.002). Also the onset age of malar rash was older in patients with II genotype than the others (II=26.7+/-8.4, ID+DD=21.3+/-9.0; P=0.021). The patients with I allele showed a significantly higher frequency of serositis (P = 0.022). Taken together, the I/D polymorphisms of ACE gene did not affect susceptibility of SLE, lupus nephritis and the vascular manifestations, including Raynaud's phenomenon, in Korean SLE patients, although the DD genotype was negatively associated with Raynaud's phenomenon among SLE patients. However, it would be valuable to evaluate the role of other genes potentially related to vascular events, such as endothelin, nitric oxide or angiotensin II receptor as well as ACE gene.     

The genotype interactions of methylenetetrahydrofolate reductase and renin-angiotensin system genes are associated with myocardial infarction.

We analyzed the evolution with age of the frequencies of the I/D polymorphism of the angiotensin I-converting enzyme (ACE), a1166c of the angiotensin II AT1 receptor (AT1R), M235T of the angiotensinogen (AGT) and A225V of their methylenetetrahydrofolate reductase (MTHFR) gene in a healthy (H) population and the subsequent comparison to age- and sex-matched groups of myocardial infarction (MI) subjects. A total of 472 H subjects were divided into three groups < 30, 30-55 and > 55 years old and 277 individuals with MI into two groups 30-55 and > 55 years old. The evolution with age showed that the AGT M allele (P < 0.001) and the MTHFR V allele (P < 0.05) frequency decreased with age in H men. The comparison between healthy and MI groups showed that the MM genotype frequency increased in MI men > 55 years (OR =4.16; 95% CI; 1.72-10.1) The cc genotype showed a similar behaviour (OR = 3.96; 95% CI; 1.21-12.9). In men, all the combinations with MM genotype presented a high risk, with OR values between 1.10 and 7.22. In women, the cc genotype increased in the MI > 55 group (OR = 6.66; 95% CI; 2.02-21.9). All the combinations with the cc genotype showed OR values between 1.71 and 13.3. The MM genotype in men and cc genotype in men and women, are independent risk factors for MI. We propose that the study of the allele frequency evolution in an H population at different ages is essential to determine risk factors for MI in case-control studies, since data from isolated age-matched groups can be misinterpreted.     

Angiotensin-converting enzyme insertion/deletion gene polymorphism in inflammatory bowel diseases

INTRODUCTION: The renin-angiotensin system is strictly related to the kallikrein-kinin system and both are involved in many physiological and disease conditions and possibly in the pathogenesis of inflammatory bowel disease (IBD). Angiotensin-converting enzyme (ACE) is the pivotal enzyme of the renin-angiotensin system and the main catabolic enzyme of the kallikrein-kinin system. The ACE I/D (insertion/deletion) is a polymorphism of the gene encoding for ACE: participants who are homozygous for the D allele exhibit higher ACE levels, which in turn appear to play a deleterious role in several diseases. AIM: To study the prevalence of ACE I/D polymorphism in IBD patients and its possible association with disease features. METHODS: A total of 232 IBD patients, 124 with ulcerative colitis (UC) and 108 with Crohn's disease and 99 healthy controls were genotyped for the ACE I/D polymorphism. RESULTS: DD, ID and II genotypes distribution did not show significant differences between IBD patients and controls: 42.2 vs. 40.4%, 42.7 vs. 47.5% and 15.1 vs. 12.1%, respectively. No significant difference was observed between Crohn's disease and UC patients. Within UC patients, the presence of DD genotype and the carriage of the D allele were significantly associated with the presence of extraintestinal manifestations: odds ratio (OR) 4.08, 95% confidence interval (CI): 1.62-10.28; P<0.003 and OR=3.07, 95% CI: 1.45-6.48; P<0.003, respectively. No significant association was found with other IBD clinical features. CONCLUSIONS: The ACE I/D polymorphism is not associated with IBDs but the D allele appears to increase the risk of developing extraintestinal manifestations in UC patients.     

Lack of sex-specific effects on the association between angiotensin-converting enzyme gene polymorphism and hypertension in Japanese.

Although several studies of molecular genetics have investigated the relevance of the ACE gene to essential hypertension, the relationship remains controversial. Some studies have recently implicated sex-specificity of this candidate gene in hypertension genetics; that is, significant linkage and association were observed in men but not in women in Caucasian populations. In particular, a male-specific association was seen between the ACE insertion/deletion (I/D) polymorphism and hypertension. This could partially explain the negative results for such an association in a number of previous studies in which the subjects were not stratified according to sex. To determine whether the ACE I/D polymorphism is related to essential hypertension in Japanese subjects, we conducted a case-control study in 701 men (387 hypertensive and 314 normotensive subjects) and 542 women (324 hypertensive and 218 normotensive subjects). The genotype distribution (or allele frequencies) and hypertension status were compared between the case and control subjects with the chi2 test statistic. We found no significant association between I/D genotype and hypertension when men and women were analyzed separately or together. The results did not change appreciably when the case group of each sex was subdivided according to more stringent criteria. The odds ratio for D-allele vs. I-allele was estimated to be 0.90 (95% CI; 0.73-1.12) in men and 0.90 (95% CI; 0.70-1.16) in women. Taken together, our data do not support the existence of a sex-specific association between the ACE I/D polymorphism and essential hypertension in the Japanese population.     

血管紧张素转换酶基因多态性与缺血性脑卒中后3个月认知的关系

目的探讨血管紧张素转换酶(ACE)基因插入/缺失(I/D)多态性与缺血性脑卒中后3个月非痴呆认知功能障碍(CIND)的关系。方法初发缺血性脑卒中患者185例,根据脑卒中后3个月认知功能测定将患者分为CIND组(42例)和对照组(143例)。PCR法测定ACE基因I/D多态性,采用简易智能状态量表和美国精神疾病统计和诊断手册第4版修订本进行认知测定。结果 CIND组与对照组ACE基因I/D多态性的基因型分布与Hardy-Weinberg平衡的理论频数之间差异无统计学意义。单因素分析发现,ACE基因DD基因型人群CIND发病风险是Ⅰ等位基因携带者的2.460倍(95% CI:1.084～5.582,P0.05)。多因素logistic回归分析发现,在共显性模式中,DD基因型人群CIND发病风险是Ⅱ基因型的3.185倍(95% CI:1.148～8.842,P0.05);在隐性遗传模式中,DD基因型人群CIND发病风险是Ⅰ等位基因携带者的2.852倍(95% CI:1.058～7.687,P0.05)。结论ACE DD基因型是缺血性脑卒中后CIND的独立危险因素,携带ACE DD基因型的患者可能更易发生CIND。     

Interaction between GNB3 C825T and ACE I/D polymorphisms in essential hypertension in Koreans

Essential hypertension (EH) is considered a typical polygenic disease, so the evaluation of gene-gene interactions rather than the determination of single gene effects is crucial to understanding any genetic influences. The G-protein beta3-subunit (GNB3) 825T allele, associated with enhanced G-protein signalling, is a strong candidate for interactions with polymorphisms, such as insertion/deletion (I/D) polymorphism of angiotensin I-converting enzyme (ACE) gene. We investigated whether there is an association between GNB3 C825T and ACE I/D polymorphisms for the development of EH. We carried out a case-control study of 688 hypertensive and 924 normotensive subjects recruited from South Korea. The GNB3 C825T and ACE I/D genotypes were determined by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism methods, respectively. The distributions of alleles and genotypes for the GNB3 C825T and ACE I/D polymorphisms were not found to be significantly associated with hypertensive status in either males or females. Logistic regression analysis indicated that the GNB3 825T allele carriers were positively associated with EH in males (odds ratio (OR) for TT/CT, 1.459; 95% confidence interval (CI), 1.048-2.033, P=0.0255). In analysis of gene-gene interaction, we found that there was a significant interaction between the GNB3 825T and ACE D alleles (P<0.05). OR for EH was significantly higher in 825T allele carriers with ACE D allele (OR, 1.490; 95% CI, 1.117-1.987, P=0.0067). A significant interaction between the GNB3 825T and the ACE D alleles may contribute to the predisposing effect for the development of EH in Koreans.