Polymorphisms of the renin-angiotensin system genes in Brazilian patients with lupus nephropathy

Genetic polymorphisms of the renin-angiotensin system (RAS) has been associated with cardiovascular events and the progression of nephropathy in several diseases. The objective of this study was to evaluate a possible association of the genetic polymorphisms of RAS with the development and/or progression of lupus nephritis in a Brazilian population. Seventy-five SLE patients with lupus nephropathy (LN group) were compared to 72 SLE patients without LN (SLE group) and 65 healthy individuals (CONTROL group), of sex and ethnic matched, in a Brazilian population sample. Mean global follow-up was 9 +/- 6 years for lupus without nephropathy and 11 +/- 7 years for lupus nephropathy. Following the extraction of genomic DNA from the leukocytes in the peripheral blood, angiotensin converting enzyme (ACE I/D), angiotensinogen (AGT M(235)T) and angiotensin II type 1 receptor (AGTR1 A(1166)C) genotypes were determined by the polymerase chain reaction. No significant difference of ACE, AGT and AGTR1 genotypes distribution between groups was observed in this study. There was no significant association between the variables of the RAS genotypes and the presence of hypertension in SLE. However, an increased frequency ofDD genotype (ACE I/D) was observed in SLE patients with LN who progressed to CRF compared to healthy controls (DD 60%, DI 26.7%, II 13.3% versus 27.7%, 60% and 12.3%, respectively; chi2 = 6.299, P = 0.0429). In the population studied, there was no influence of the RAS genetic polymorphisms in the development of lupus nephropathy, but the progression to CRF was associated with ACE DD polymorphism.     

Angiotensin-converting enzyme gene polymorphism in Kuwaiti patients with systemic lupus erythematosus

OBJECTIVE: To investigate the frequency of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism genotypes in patients with systemic lupus erythematosus (SLE), and to study the correlation between I/D polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement, lupus nephritis and disease severity. METHODS: The frequency of ACE gene I/D polymorphism genotypes was determined in 92 patients with SLE from Kuwait, and compared to that in 100 ethnically matched healthy controls using the polymerase chain reaction. RESULTS: The distribution of ACE I/D polymorphism and allele frequencies in SLE patients was not significantly different from controls. Further analyses of SLE patients showed that there was a significant association between DD genotype and Raynaud's phenomenon (p=0.008, odd ratio=5.4, 95% confidence interval: 1.6-18.6). However, there was no significant association between the ACE genotype and lupus nephritis or disease severity. CONCLUSION: No difference was found between the distribution of the ACE genotype in SLE patients and the general pop-ulation in Kuwait. However, the presence of the DD genotype may confer susceptibility to the development of vascular morbidity.     

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.     

Angiotensin-converting enzyme (insertion/deletion) and endothelial nitric oxide synthase polymorphisms in patients with systemic lupus erythematosus

OBJECTIVE: Genetic polymorphisms in the angiotensin-converting enzyme (ACE) and endothelial nitric oxide synthase (eNOS) are linked with expression and/or progression of renal disease. We hypothesized that polymorphisms in the genes coding for ACE and eNOS may influence the development and/or progression of systemic lupus erythematosus (SLE) and lupus nephritis given their linkage with other renal diseases. METHODS: DNA from patients with SLE (n = 227) and their age and sex matched controls (n = 275) from the Carolina Lupus (CLU) Study cohort was assessed for ACE and eNOS polymorphisms. Seventy patients had biopsy-proven lupus nephritis. Two different eNOS polymorphisms (eNOS promoter T-786(R)C nucleotide substitution and eNOS 27 base pair tandem repeat in intron 4) and the ACE insertion/deletion (I/D) polymorphism in intron 16 were examined by restriction fragment length polymorphism-polymerase chain reaction. RESULTS: Allele frequency of the eNOS polymorphisms varied significantly between SLE patients and controls. There was no association of these polymorphisms with lupus within ethnic groups. We found no association of the polymorphism with the development of renal disease. No association was observed for the ACE I/D polymorphism with SLE or nephritis, or with ethnicity or sex. CONCLUSION: eNOS genetic polymorphisms differed significantly across ethnic groups. There was no significant increased risk of SLE and/or lupus nephritis associated with eNOS or ACE polymorphisms in either the African American or Caucasian groups compared to ethnically matched controls. These studies emphasize the need to control for ethnicity when investigating genetic polymorphisms and disease.     

Association between systemic lupus erythematosus and insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene.

OBJECTIVE: ACE takes part in the renin-angiotensin and kallikrein-kininogen systems by creating angiotensin-II and inactivating bradykinin. ACE gene insertion/deletion polymorphism is associated with the level of circulating enzymes--subjects with the DD genotype have higher levels of circulating ACE than subjects with the II genotype and show an increased tendency towards impaired vascular function and structure. Patients with systemic lupus erythematosus (SLE) suffer from differentially expressed vascular pathology. We attempted to determine whether the type of ACE polymorphism could contribute to this pathology. METHODS: 101 SLE patients fulfilling the ACR criteria were investigated. The I/D polymorphism was ascertained by PCR, followed by electrophoresis of the amplified fragments and UV visualization. RESULTS: The frequency of the D allele was higher in the SLE group (0.623) than in the controls (0.520) (chi 2 test, p < 0.025). The distribution of the ACE genotype in SLE group was different from that in the control group (p < 0.05). An association between the DD genotype and visceral damage (p < 0.006) was observed. CONCLUSION: Our results suggest that in the multifactorially determined vascular pathology of SLE, changes associated with I/D polymorphism could influence vessel wall inflammation (monocyte adhesion and activation with cytokine release, T-lymphocyte metabolism), a tendency towards vascular impairment (neointimal proliferation, vasospasm, platelet activation, myocyte proliferation) and lead to the subsequent ischemia. The ACE gene could serve as the visceral damage indicator in SLE.     

Tumor necrosis factor-alpha promoter -308 A/G polymorphism and rheumatoid arthritis susceptibility: a metaanalysis

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) promoter -308 A/G polymorphism has been reported to be associated with rheumatoid arthritis (RA) with inconsistent results. We investigated whether TNF-alpha -308 A/G polymorphism confers susceptibility to RA. METHODS: We conducted a random effect metaanalysis on the association of genotypes A/A (recessive effect), A/A + A/G (dominant effect), A allele, and A/A vs G/G genotypes of the TNF-alpha -308 polymorphisms with RA overall and within different ethnic populations. RESULTS: Fourteen studies, 10 of Europeans, 3 of Latin Americans, and one Asian, were included in this metaanalysis. An association between RA and the TNF-alpha -308 A allele was not found in the overall population (OR 1.005, 95% CI 0.715-1.412, p = 0.976). However, stratification by ethnicity indicated that the TNF-alpha A allele was significantly associated with RA in Latin Americans (OR 2.004, 95% CI 1.158-3.467, p = 0.013). Conversely, there was no association detected for the TNF-alpha A allele with RA patients from the European samples (OR 0.911, 95% CI 0.684-1.212, p = 0.520). The OR for the A/A + A/G genotype, the A/A genotypes, and the A/A vs G/G genotypes in samples overall and in each ethnic group showed a similar trend to those for the TNF-alpha A allele. CONCLUSION: This metaanalysis demonstrates that the TNF-alpha -308 A/G polymorphism may represent a significant risk factor for RA in Latin Americans, but not in Europeans.     

ACE and TGFBR1 genes interact in influencing the susceptibility to abdominal aortic aneurysm

A role of ACE I/D polymorphism in the pathogenesis of abdominal aortic aneurysm (AAA) has been demonstrated, possibly due to the effect of angiotensin II on vascular tissue remodelling. Angiotensin II exerts profibrogenic effects through the local induction of TGF-beta. Dysregulated TGF-beta signalling may result from mutations in TGFBR1 and TGFBR2 genes, thus resulting in degenerative changes in the vessel wall. We performed a case-control study in order to investigate the role of TGFBR1 9A6A polymorphism as predisposing factor to AAA per se, and in the presence of ACE DD and AT1R 1166 CC genotypes in 201 AAA patients (mean age+/-S.D., 71.5+/-6.9) referred to the Unit of Vascular Surgery of the University of Florence, compared with 252 healthy controls (mean age+/-S.D., 70.6+/-8.6). A significant difference in genotype distribution and allele frequency between patients and controls was found for ACE, but not for AT1R and TGFBR1 polymorphisms. At univariate analysis a significant association between ACE DD, but not AT1R CC and TGFBR1 6A allele, and the susceptibility to the disease was found [ACE DD OR=1.86 (95% CI 1.26-2.76), p=0.002]. After adjustment for age, gender, traditional cardiovascular risk factors, and CAD, PAD and CVD, ACE DD genotype still affected the susceptibility to AAA [OR=2.13 (95% CI 1.06-4.28), p=0.03], and the contemporary presence of ACE DD genotype and TGFBR1 6A allele, increased the predisposition to the disease [OR=5.09 (95% CI 1.44-18.02), p=0.01]. This study, which demonstrates an interaction between ACE and TGFBR1 genes in predisposing to AAA, may provide further information on the mechanisms contributing to AAA susceptibility, and offer a topic for future larger studies.     

脑出血患者载脂蛋白E和血管紧张素转换酶的基因多态性分析

目的探讨载脂蛋白E（apoliportein E,ApoE）和血管紧张素转换酶（angiotensin converting enzyme,ACE）基因多态性与脑出血的关系。方法应用聚合酶链反应-限制性片断长度多态性技术检测80例脑出血患者和90名健康对照者的ApoE和ACE基因型和等位基因。并运用Logis-tic回归分析ApoE和ACE基因多态性与脑出血的相关性。结果脑出血组ApoE的基因型频率和等位基因频率与正常对照组比较,差异均无统计学意义,P〉0.05;ACE的DD基因型频率为35.0%,D等位基因频率为51.9%,明显高于正常对照组的15.6%、38.9%,均P〈0.05;Logistic回归分析显示,ACE的DD基因型的患者患脑出血的OR值为2.923（95%CI：1.406-6.079）;同时携带ACE基因DD型和ApoE E3/4基因型的患者患脑出血的OR值为3.428（95%CI：1.045-11.237）。结论ACE基因插入/缺失多态性可能是脑出血发病的独立遗传因素;与ApoE基因多态性间具有协同致脑出血的作用。     

ACE基因I/D多态性与系统性红斑狼疮肾脏易感性关系的研究

研究血管紧张素转换酶基因Ｉ／Ｄ多态性与系统性红斑狼疮肾脏易感性的关系。方法用ＰＣＲ法和比色法分别测定５８例ＳＬＥ患者和４０例正常人的ＡＣＥ基因型和血清ＡＣＥ活性。结果确诊ＳＬＥ时临床有肾脏受累表现组ＡＣＥ基因ＤＤ型和Ｄ等位基因分布频率明显高于组，且ＤＤ型、ＤＩ型者血清ＡＣＥ活性前者明显于高于后者。     

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.     

Renal outcome and vascular morbidity in systemic lupus erythematosus (SLE): lack of association with the angiotensin-converting enzyme gene polymorphism

OBJECTIVES: The angiotensin-converting enzyme (ACE) gene polymorphism has been associated with worse outcome in various chronic glomerular disorders and in hypertension. Because nephritis and vascular morbidity are prominent determinants of outcome in systemic lupus erythematosus (SLE), we studied the distribution and prognostic effect the ACE genotype might have on the outcome of SLE. METHODS: Fifty-six consecutive Israeli SLE patients and 48 (sex and ethnic origin matched) healthy individuals were evaluated for the ACE genotype by a polymerase chain reaction-based assay. The clinical and laboratory parameters of the patients as well as the SLE disease activity index (SLEDAI) and the presence of hypertension, diabetes mellitus, ischemic heart disease, congestive heart failure, and stroke were correlated with the ACE genotype. RESULTS: The distribution of the ACE genotype D/D, D/I, and I/I in the lupus group was 59%, 36%, and 5%, respectively, similar to the distribution in the control group (54%, 31%, and 15%, respectively). We failed to find any significant association between the ACE genotype and disease manifestations, SLEDAI, renal function, or cardiovascular and cerebrovascular morbidity. The clinical and laboratory parameters associated with renal outcome and vascular morbidity in our cohort are described. CONCLUSIONS: No difference was found between the distribution of the ACE genotype in lupus patients and the general population in Israel. Renal function as well as cardiovascular and cerebrovascular morbidity among Israeli patients with SLE are disease-related and independent of the ACE gene polymorphism.     

Searching for a better assessment of the individual coronary risk profile. The role of angiotensin-converting enzyme, angiotensin II type 1 receptor and angiotensinogen gene polymorphisms.

BACKGROUND: Polymorphisms within renin angiotensin system genes have been investigated as risk factors for coronary artery disease in different populations with contradicting results. The aim of this study was to investigate the genotype distribution and the allele frequencies of ACE, AT1R and AGT gene polymorphisms as coronary artery disease factors and their synergistic effects on coronary risk in an Italian population. METHODS AND RESULTDS: In this study ACE, AT1R and AGT gene polymorphisms were investigated in 205 consecutive coronary artery disease patients and in 209 controls. These polymorphisms were analysed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The ACE D and AGT 235T allele, but not AT1R C allele, frequency was statistically significant in patients. An association between coronary artery disease and ACE DD, AT1R CC and AGT TT genotype, was found by univariate analysis (OR 2.06 P=0.0007, OR 2.49 P=0.009, OR 1.87 P=0. 019, respectively). At multivariate analysis ACE DD and AT1R CC genotype (OR 1.81 P=0.011, OR 2.61 P=0.011, respectively) remained associated with coronary heart disease. Subjects carrying the ACE DD genotype and AT1R C allele showed a stronger association with myocardial infarction (OR=4.02, P<0.0001). CONCLUSION: Our report indicates the increased risk of coronary artery disease in the presence of ACE DD and AT1R CC genotypes independent of other risk factors, in Italian patients. The present study stresses the relevance of screening for genetic risk factors.     

Association between vitamin D receptor gene BsmI,FokI, ApaI and TaqI polymorphisms and the risk of systemic lupus erythematosus: a meta-analysis

Association studies of vitamin D receptor (VDR) gene polymorphisms and the risk of systemic lupus erythematosus (SLE) have yielded conflicting results in different backgrounds. We aimed to evaluate the association between VDR gene polymorphisms and SLE risk. A predefined electronic databases search was performed to identify eligible studies that were related to the association of VDR gene BsmI, FokI, ApaI or TaqI polymorphism with SLE risk. Either a fixed-effects model, or in the presence of heterogeneity, a random-effects model was used to calculate the pooled odds ratios (ORs) and its corresponding 95 % confidence interval (CI). A total of 11 studies with 1,621 cases and 1,883 controls were included in this meta-analysis. BsmI B allele was associated with the onset of SLE for overall populations (OR 1.726, 95 % CI 1.214–2.455) and Asians (OR 1.952, 95 % CI 1.135–3.355). FokI FF genotype was correlated with the susceptibility of SLE for Asians (OR 1.469, 95 % CI 1.005–2.148). FokI T/C and TaqI polymorphisms were not associated with SLE risk for Caucasians. There was no significant association between ApaI polymorphism and SLE risk for overall populations, Asians and Caucasians. No evidence of publication bias was observed. In conclusion, BsmI B allele may be a risk factor for SLE onset among overall populations and Asians, and FokI FF genotype is a risk factor for SLE susceptibility in Asians. However, more studies should be performed in the future.     

The ACE insertion/deletion polymorphism and its association with metabolic syndrome

The angiotensin-1-converting enzyme (ACE) gene has been suggested to be involved in the development of metabolic syndrome (MetS). However, results have been inconsistent. In this study, a meta-analysis was performed to investigate the association between ACE insertion/deletion (I/D) polymorphism and MetS. Published literature from PubMed, EMBASE, and ISI Web of Science databases was searched for eligible publications. All studies assessing the association between ACE I/D polymorphism and MetS were included. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated using a fixed- or random-effects model. Ten studies (1939 cases/2845 controls) for ACE I/D polymorphism were included in this meta-analysis. Most of the studies were performed in whites. The ACE I/D polymorphism was associated with an increased OR of MetS under a dominant model (DD + ID vs II: OR = 1.39; 95% CI, 1.22-1.60; P < .001). Using this model, similar results were found among studies using different ethnic populations, studies using different MetS definitions, and studies with more than 100 cases. This meta-analysis indicated that the D allele of the ACE gene, known to be related to higher levels of angiotensinogen, is associated with an increased OR of MetS. However, given the limited sample size, this association warrants further investigation.     

肾素-血管紧张素系统基因多态性与原发性高血压左心室肥厚关系的探讨

目的　探讨肾素 血管紧张素系统 (RAS)基因多态性与原发性高血压左心室肥厚 (EH LVH)的相关性以及在EH LVH产生中的多基因协同作用。方法　对 10 9例原发性高血压病 (EH)患者 ,采用聚合酶链反应 (PCR)以及聚合酶链反应 限制性片段长度多态性方法检测血液白细胞染色体DNA中血管紧张素转换酶 [ACE(I D) ]、血管紧张素原 [AGT(M2 35T) ]和血管紧张素Ⅱ 1型受体 [AT1 R(A116 6C) ]基因多态性 ;利用超声心动图检测左心室质量 (LVM)并计算左心室质量指数 (LVMI)。结果　ACE(I D)基因多态性D等位基因频率在EH LVH组中明显增高 (χ2 =4 .6 9,P=0 .0 30 ) ,男性EH患者中 ,ACE(I D)基因型构成比与LVH有关联 (χ2 =9.5 5 ,P =0 .0 0 8)。协同存在AGT TT型时 ,ACE(I D)基因多态性与EH LVH有关 (χ2 =6 .2 2 ,P =0 .0 4 4 ) ,且D等位基因在EH LVH明显增高 (χ2 =6 .91,P =0 .0 0 9) ,该类EH患者发生LVH的相对危险度增高 (OR :2 .5 0 ,95 %CI:1.2 5～ 5 .0 0 )。结论　ACE(I D)基因多态性D等位基因可能是LVH的独立危险因子。ACE基因多态性与AGT基因多态性之间的协同效应表明 ,同时携带AGT TT型时 ,具有ACE(I D)基因多态性D等位基因的EH患者更易发生LVH。     

Association of the G-463A myeloperoxidase gene polymorphism with renal disease in African Americans with systemic lupus erythematosus

OBJECTIVE: Myeloperoxidase (MPO) is an enzyme expressed in neutrophils that is involved in tissue damage in inflammatory renal diseases. A functional G to A single-nucleotide polymorphism (SNP) is present at position -463 of the MPO promoter region and is associated with altered MPO expression. We hypothesized that the G-463A MPO SNP is a risk factor for developing lupus nephritis (LN) due to its potential influence on the inflammatory response. METHODS: DNA from 229 patients with SLE and 277 controls from the Carolina Lupus cohort, 58 African American patients from the Sea Island Lupus Cohort, and 51 African American patients from the Lupus Multiplex Registry and Repository were genotyped by PCR. A linear regression model was used to examine relationships between the MPO genotype, case/control status, demographic characteristics, and LN. RESULTS: There was no association of MPO genotype with systemic lupus erythematosus (SLE). However, the odds of developing LN were significantly higher among those with an A allele, compared to those without, in African American cases of all 3 cohorts. When the likelihood of developing LN was compared across MPO genotypes, the risk of developing LN was significantly higher among cases with a GA genotype versus GG (OR 2.11, 95% CI 1.12 to 3.97) and even higher with AA versus GG (OR 3.52, 95% CI 1.41 to 8.77). CONCLUSION: While the G-463A MPO SNP is not a risk factor for developing SLE, the low expressing A allele is a significant risk factor for developing LN that is gene dosage-dependent in African Americans.     

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。     

血管紧张素原基因T174M和血管紧张素转换酶基因I/D多态性与急性心肌梗死的相关性

目的探讨中国汉族人群血管紧张素转换酶和血管紧张素原基因型的分布及其与急性心肌梗死的关系。方法应用聚合酶链反应技术,对112例急性心肌梗死患者、128例非冠心病患者血管紧张素转换酶I/D多态性及血管紧张素原T174M多态性进行检测。结果血管紧张素转换酶基因型分布及等位基因频率在病例组及对照组间差异有显著性(P<0.01)。病例组和对照组血管紧张素原基因型及等位基因频率总体分布差异亦有显著性(P<0.05)。联合基因分析显示,急性心肌梗死组血管紧张素转换酶DD基因型 血管紧张素原174MM基因型频率显著高于对照组(P<0.01),具有该联合基因型者发生冠心病的风险比数比(OR=8.467)明显高于单独具有血管紧张素转换酶DD基因型(OR=2.558)或血管紧张素原174MM基因型(OR=6.176)者。结论血管紧张素原T174M基因多态性中M等位基因和血管紧张素转换酶I/D基因多态性基因中的D等位基因是中国汉族人群冠心病发病的危险因素之一。同时具有血管紧张素转换酶DD型及血管紧张素原174MM型发生冠心病的相对风险显著高于单基因血管紧张素转换酶DD型及单基因血管紧张素原174MM型。     

Population-based case-control study of renin-angiotensin system genes polymorphisms and hypertension among Hispanics.

The effect of polymorphisms of the RAS genes on the incidence of hypertension seems to be population-dependent. We studied the effects of the angiotensinogen T174M and M235T, angiotensin converting enzyme insertion/deletion (ACE I/D), and angiotensin II receptor 1 (AT1R) A1166C gene polymorphisms on the risk of hypertension among Hispanics. We selected all cases (n=256) and 257 age and sex group-matched controls from a random sample of free living Colombians (n=2,989). Logistic regression was used to estimate the independent effect of each polymorphism. All polymorphisms were in Hardy-Weinberg equilibrium in controls, with the exception of M235T, which showed a small excess of heterozygotes (p=0.005; disequilibrium coefficient, D=-0.0264). After adjustment for age, sex, body mass index, race, physical activity, family history of hypertension and cardiovascular disease, and other polymorphisms, subjects with the ACE DD genotype were 1.56 times (95% confidence interval [CI]: 1.05, 2.33) more likely to be hypertensive than carriers of the I allele (p=0.03). Also, adjusted systolic and diastolic blood pressure were 4.58 (95% CI: -0.39, 9.56) and 3.32 (95% CI: 0.78, 5.86) mmHg higher in DD homozygous individuals than in carriers of the I allele, respectively. Approximately 15% of the cases of hypertension in this population could be attributed to carriage of the DD genotype. None of the other polymorphisms was associated with either hypertension or blood pressure level. In conclusion, the ACE DD genotype appears to be an independent risk factor for development of hypertension and may explain a significant fraction of incident cases among Hispanics.     

A population study of ethnic variations in the angiotensin-converting enzyme I/D polymorphism: relationships with gender, hypertension and impaired glucose metabolism.

BACKGROUND: The presence of the deletion allele of the angiotensin-converting enzyme (ACE) I/D polymorphism is associated with an excess risk of vascular disease and diabetic nephropathy. OBJECTIVE: To examine the importance of this polymorphism as a determinant of hypertension and impaired glucose metabolism in a population-based study of three ethnic groups and assess the potential modifying effect of gender. DESIGN: Population-based cross-sectional study in South London. The population-based sample of 1577 men and women, age 40-59 years, was obtained from stratified random sampling of general practice lists where 25% of the residents were born outside the UK. The ACE I/D polymorphism was determined for 1366 individuals (86.6%): 462 whites, 462 of African descent and 442 of South Asian origin. RESULTS: The genotype frequency within each ethnic group was in Hardy-Weinberg equilibrium. The frequencies were similar in whites and those of African descent (II, ID, DD: 18.4%, 49.6%, 32.0% for whites and 18.4%, 50.5%, 30.9% for those of African descent), but there was a much higher frequency of the II genotype in those of South Asian origin (39.8%, 41.8%, 18.3%; chi2 = 77.6; P < 0.0001). There was no association between the I/D polymorphism and impaired glucose metabolism in any ethnic group. There were also no significant associations between the I/D polymorphism and hypertension in whites and in those of South Asian origin. This contrasts with a highly significant association between the D allele and hypertension in women of African descent (OR = 2.54; 95% CI 1.38-4.65; P = 0.003) but not in men of African descent (0.79; 0.36-1.72) (test for differences between sexes P = 0.023). CONCLUSIONS: These observations provide estimates of the frequency distribution of the ACE I/D polymorphism in whites, in people of African descent and in people of South Asian origin. Moreover, these results highlight the potential importance of gender-dependent interactions between genetic background and expression of hypertensive phenotype.