Genotype-specific association between circulating soluble cellular adhesion molecules and carotid intima-media thickness in community residents: J-SHIPP study. Shimanami Health Promoting Program.

Plasma levels of soluble forms of cellular adhesion molecules (CAMs) and their relationships with carotid intima-media thickness (IMT) were investigated in community residents. Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured by ELISA in 200 community residents in Japan. Carotid IMT showed a weak but significant positive correlation with the plasma levels of both sICAM-1 (r=0.175, p=0.013) and sVCAM-1 (r=0.19, p=0.0075). Gene polymorphisms of angiotensin converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) M235T, angiotensin II type 1 receptor (AT1R) A1166C and apolipoprotein E (apoE) were determined for each subject. The plasma level of sVCAM-1 tended to be lower in subjects with the ACE DD genotype than in those with the ACE ID and II genotypes (373+/-94, 421+/-133, 443+/-135 ng/ml, respectively, p=0.056). However, there were no genotype-specific differences in the plasma levels of soluble forms of CAMs for the other genes examined. In a separate analysis, the plasma level of sICAM-1 was significantly associated with carotid IMT in ACE D carriers (ID + DD) (r=0.28, p=0.002), AGT M carriers (MT + MM) (r=0.32, p=0.0045), and subjects with apoE4 (r=0.35, p=0.036). In contrast, the plasma level of sVCAM-1 showed significant positive correlations with carotid IMT in subjects with the ACE II genotype (r=0.33, p=0.0027) or AGT TT genotype (r= 0.22, p=0.015), and subjects with apoE E2/E3 or E3/E3 (r=0.16, p=0.043). Stepwise regression analysis showed that plasma sVCAM-1 was independently associated with carotid IMT in subjects with the ACE II genotype or apoE4 genotype. Similarly, the plasma level of sICAM-1 was independently associated with carotid IMT in AGT M carriers. These findings suggest that genetic background could be involved in the association between plasma CAMs and atherosclerosis.     

Gene polymorphisms of the renin-angiotensin system and early development of hypertension

BACKGROUND: A case-control association study was conducted to investigate a possible involvement of polymorphisms of three renin-angiotensin system genes: ACE (I/D and T-3892C), AGT (M235T and T174M), and AT1R (A1166C) in the early development of hypertension. METHODS: One hundred nineteen hypertensive and 125 normotensive participants aged 18 to 40 years were selected from a broader sample representative of the general population of Croatia. The selection criteria for hypertensive cases were systolic blood pressure (BP) higher than 140 mm Hg or diastolic BP higher than 90 mm Hg and a history of hypertension according to patient interview. RESULTS: Among the polymorphisms investigated, only those located on the ACE gene were associated with hypertension. For ACE I/D, the odds ratio for hypertension of DD versus II homozygote individuals was 2.50 (95% confidence interval [CI] 1.19-5.25) and for ACE T-3892C, the odds ratio of CC versus TT individuals was 2.32 (95% CI 1.05-5.10). Both polymorphisms of the ACE gene were in tight linkage disequilibrium. Of the investigated risk factors for hypertension, only body mass index (BMI) showed an influence on the early development of hypertension, acting independently of the ACE polymorphism. Their additive effect gives rise to 86% of hypertensives in subjects having both the DD genotype and BMI >or=30 kg/m(2). CONCLUSIONS: The present study provides evidence of the association of the ACE gene polymorphisms and premature hypertension. In addition, BMI proved to be another important predictor of the disorder acting independently of the ACE gene.     

Relationship between polymorphisms in the renin-angiotensin system and nephropathy in type 2 diabetic patients

BACKGROUND: Renin Angiotensin system is involved in renal function and its polymorphisms may influence diabetic nephropathy. ID ACE polymorphism modulates ACE level whereas M235T AGT polymorphism is involved in arterial hypertension. The A1166C AT1R polymorphism is involved in arterial hypertension and in diabetic retinopathy.METHODS: Two hundred thirty five type 2 diabetic patients were enrolled in this transversal study. Data were documented for clinical characteristics of the population, HbA(1c), urinary albumin excretion, presence of retinopathy or antihypertensive treatment. Polymorphisms were analyzed by PCR techniques. The patients were divided into 3 groups: group 1, without nephropathy (n=118), group 2, microalbuminuria (n=78), group 3, macroalbuminuria (n=39).RESULTS: Diabetes duration was longer (p<0.001), retinopathy (p<0.001) and antihypertensive treatment (p<0.02) were more frequent in group 3 compared to group 1 and 2. The I/D ACE and M235T AGT polymorphisms were not differently distributed between the three groups. In contrast, the CC genotype of the AT1R polymorphism was overrepresented in group 2 (p=0.021). The presence of the CC AT1R genotype considerably increased the incidence of albuminuria after 10 years of diabetes (AA vs CC p=0.01), particurlarly in men. No effect was seen with I/D ACE and M235T AGT polymorphisms.CONCLUSION: In conclusion, we observed an interaction of A1166C AT1R polymorphism with diabetes in men but not of I/D ACE and M235T AGT polymorphisms.     

CYP11B2 -344T/C gene polymorphism and blood pressure in patients with acromegaly

CONTEXT: The pathogenesis of increased blood pressure (BP) in acromegaly is unclear, and the role of IGF-I levels and the renin-angiotensin-aldosterone system (RAAS) in this disease remains controversial. OBJECTIVE AND DESIGN: The aim of this study was to investigate the role of gene polymorphisms of the RAAS and involved in sodium handling on BP in acromegaly. SETTING AND PATIENTS: We conducted a multicentric retrospective study that included 100 consecutive patients with acromegaly referred during the period 2000-2003. INTERVENTION: All patients were genotyped for ACE I/D, AGT M235T, CYP11B2 -344T/C, B2R -58T/C, and alpha-adducin G460W polymorphisms. MAIN OUTCOME MEASURE: We assessed the prevalence of hypertension and BP according to the genotype. RESULTS: Patients with the CYP11B2 -344CC genotype displayed a significant increase in the risk of hypertension compared with patients with CT/TT genotypes (odds ratio = 4.0; 95% confidence interval = 1.4-11.6; P = 0.01). Consistently, a significant proportion of patients with the CYP11B2 -344CC genotypes were under antihypertensive treatment (73.1%) compared with patients with the TT/TC genotypes (38.2%; P = 0.003). Patients with the -344CC genotype displayed a significant increase in systolic BP (10.2 +/- 4.3 mm Hg; P = 0.02) but not a significant increase in diastolic BP (2.6 +/- 2.6 mm Hg; P = 0.32) compared with patients with the CT/TT genotype. CONCLUSIONS: We have shown an association of the -344T/C CYP11B2 gene polymorphism with BP in patients affected by acromegaly. These findings suggest that the RAAS is implicated in the pathogenesis of hypertension in acromegaly.     

beta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the Cardiovascular Health Study

BACKGROUND: Common Arg16Gly and Gln27Glu polymorphisms of the beta(2)-adrenergic receptor (beta(2)AR) have been associated with hypertension and coronary disease. This analysis of older adults in the Cardiovascular Health Study examined whether these polymorphisms were associated with blood pressure (BP), subclinical atherosclerosis, and, among treated hypertensive individuals, differences in coronary disease risk according to antihypertensive drug class. METHODS: Altogether, 5249 participants (4441 white and 808 African American, median follow-up time 10.2 years) were genotyped for both polymorphisms. Ankle-arm index (AAI), carotid intima-media thickness (IMT), and brachial flow-mediated dilation were measured cross-sectionally. All estimates were adjusted for ethnicity. RESULTS: Relative to Gln27 homozygotes, carrying the Glu27 allele was not associated with new-onset hypertension (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 0.87 to 1.16), BP control (odds ratio [OR] = 0.97, 95% CI = 0.89 to 1.06), AAI (mean difference 0.0042 +/- 0.0052), carotid IMT (mean difference 0.0044 +/- 0.02 mm), or brachial flow-mediated dilation (mean difference in baseline diameter -0.028 +/- 0.036 mm; the most marked of three measures). Among treated hypertensive individuals, coronary disease risk was similar in Glu27 carriers relative to Gln27 homozygotes in subgroups defined by use of beta-blockers (HR = 1.09, 95% CI = 0.64 to 1.87) or other antihypertensive medications (HR = 1.00, 95% CI = 0.78 to 1.28). Results were similar for the Arg16Gly polymorphism. CONCLUSIONS: The association of beta(2)AR genotype with coronary disease previously reported in this older adult population is not likely to be explained by BP levels, subclinical atherosclerosis, or antihypertensive treatment. Other measures of vascular response, gene-gene or gene-environment interactions, or characteristics developing earlier in life may mediate the association between beta(2)AR genotype and coronary disease and merit further research.     

Genetic polymorphisms of angiotensin-I converting enzyme, haptoglobin and angiotensinogen and oxidative stress parameters in 12 to 15-year-old adolescents.

BACKGROUND: Angiotensin-converting enzyme (ACE) I/D, haptoglobin (Hp) 1/2 and angiotensinogen (AGT) M235T gene polymorphisms have been associated with the risk of various cardiovascular conditions. Oxidative stress and reactive oxygen species have also been implicated in endothelial injury. In a randomly selected sample of healthy adolescents, we studied the relationship between these genetic polymorphisms and somatic characteristics, blood pressure and certain biochemical markers of oxidative stress. METHODS: A sample of 49 healthy adolescents were genotyped for ACE I/D, Hp 1/2 and AGT M235T polymorphisms. Anthropometric parameters, blood pressure and lipid profile were evaluated using internationally recommended methods. Serum ACE activity and oxidative stress markers were determined either by spectrophotometric methods or with commercially available kits. RESULTS: Males had higher values for ACE activity than females (p < 0.01). The haptoglobin Hp allele 1 and the ACE D allele were associated with higher ACE activity (p < 0.05 and p < 0.001). ACE activity was similar between AGT genotypes. Higher levels of MDA-LDL/Apo B were observed in individuals with both ACE DD and Hp 2-2 genotypes. Carriers of the AGT TT genotype showed higher diastolic blood pressures than other AGT genotypes. CONCLUSION: Carriers of both ACE DD and Hp 2-2 genotypes have a higher pro-oxidant status and AGT TT carriers have higher diastolic blood pressures, which may indicate a higher risk for development of hypertension in these individuals.     

A/C1166 gene polymorphism of the angiotensin II type 1 receptor (AT1) and ambulatory blood pressure: the Ohasama Study.

We previously investigated the relation between hypertension and each of three major genetic polymorphisms in the renin-angiotensin (AGT)-aldosterone system (R-A-A), AGT M235T, angiotensin convert enzyme (ACE) I/D, and CYP11B2 -344C/T, by means of ambulatory blood pressure (ABP) monitoring in a general Japanese population (the Ohasama Study). A/C1166 gene polymorphism in the 3' untranslated region of the angiotensin II type 1 receptor (AT1) gene is the final remaining major target in R-A-A to be examined in the Ohasama Study population. In the present study, the AT1 A/C1166 polymorphism was genotyped by the TaqMan polymerase chain reaction (PCR) method or restriction fragment length polymorphism (RFLP) in 802 Japanese subjects aged 40 and over, who were previously genotyped for the AGT M235T, ACE D/I, CYP11B2 -344C/T polymorphisms. The AA genotype, AC genotype, and CC genotype were present in 678 (84.5%), 121 (15.1%), and 3 (0.4%) of subjects, respectively. Since the frequency of the C allele was quite low (0.079), the genotypes were classified according to the presence or absence of the C allele. Although daytime blood pressure (BP) was higher in subjects with the C allele, the difference was not statistically significant after adjusting for age, gender, body mass index, and smoking status. No significant difference was noted in the prevalence of cardiovascular diseases or nocturnal BP decline between the two groups. These results indicated that AT1 A/C1166 polymorphism was not associated with any clinical parameters associated with hypertension or atherosclerosis in the Japanese population.     

Carotid and femoral artery stiffness in relation to three candidate genes in a white population

Different genetic polymorphisms influence cardiovascular disease. We recently discovered a relationship between the intima-media thickness of the muscular femoral artery, but not the elastic common carotid artery, and the combined ACE (ACE, I/D), alpha-adducin (Gly460Trp),and aldosterone synthase (AS, C-344T) gene polymorphisms. To investigate the relationship between these polymorphisms and functional properties of the carotid artery and femoral artery, a sample of 756 subjects enrolled in a population study were genotyped for the presence of the ACE D, alpha-adducin 460Trp, and aldosterone synthase -344T alleles. Vessel wall properties were assessed using a vessel wall movement detector system in combination with applanation tonometry. Statistical analysis allowed for confounders and interaction among genes. Cross-sectional compliance of the common carotid artery was negatively associated with the ACE D allele. ACE II versus ACE DD homozygotes differed, expressed as a percentage of the population mean (7.0%; 95% confidence interval [CI], 1.6% to 12.4%; P=0.02). In multigene analysis, ACE DD subjects also deviated significantly from the population mean for the distensibility coefficient of the common carotid artery when carrying the AS/T allele (-5.5%; 95% CI, -9.3% to -1.7%; P<0.01), without a change in cross-sectional compliance. ACE DD subjects, when homozygote for alpha-adducin Gly460, had a lower femoral cross-sectional compliance (-10.4%; 95% CI, -1.9% to -18.9%; P<0.03) and a lower distensibility (-9.7%; 95% CI, -2.1% to -17.3%; P<0.02) compared with the population mean. These data show that functional large artery properties are influenced by the ACE I/D polymorphism. Cross-sectional compliance and distensibility coefficients are influenced by the ACE I/D genotype, but this influence depends on the vascular territory and genetic background.     

Polymorphism in the angiotensin converting enzyme but not in the angiotensinogen gene is associated with hypertension and type 2 diabetes: the Skaraborg Hypertension and diabetes project

OBJECTIVE: To study the association between polymorphisms in the angiotensin converting enzyme (ACE) gene and angiotensinogen (AGT) gene and hypertension and/or type 2 diabetes in a community population. PATIENTS AND METHODS: The insertion (I)/deletion (D) polymorphism of the ACE gene and the M235T polymorphism of the AGT gene were genotyped in 773 nondiabetic individuals with hypertension, 193 normotensive patients with type 2 diabetes, 243 patients with type 2 diabetes and hypertension, and in 820 normotensive control individuals identified in a community-based study. RESULTS: The DD genotype was associated with hypertension in individuals less than 70 years [odds ratio (OR) = 1.54, confidence interval (CI) = 1.09-2.18] and remained so when patients with type 2 diabetes were excluded from the analysis (OR = 1.45, CI = 1.01-2.09). The strongest association was with the combination of type 2 diabetes and hypertension (OR = 2.19, CI = 1.09-4.38). There was no association with type 2 diabetes without hypertension. No association was observed between the M235T variant or the 3'-microsatellite polymorphism of the AGT gene and hypertension. CONCLUSION: The D-allele of the ACE gene ID polymorphism increases susceptibility to hypertension, particularly when associated with type 2 diabetes. No association was observed between the M235T variant or 3'-microsatellite polymorphism of the AGT gene and hypertension.     

Progression of kidney disease in type 2 diabetes – beyond blood pressure control: an observational study

Background

Essential hypertension is a common, polygenic, complex disorder resulting from interaction of several genes with each other and with environmental factors such as obesity, dietary salt intake, and alcohol consumption. Since the underlying genetic pathways remain elusive, currently most studies focus on the genes coding for proteins that regulate blood pressure as their physiological role makes them prime suspects. The present study examines how polymorphisms of the insertion/deletion (I/D) ACE and M235T AGT genes account for presence and severity of hypertension, and embeds the data in a meta-analysis of relevant studies.

Methods

The I/D polymorphisms of the ACE and M235T polymorphisms of the AGT genes were determined by RFLP (restriction fragment length polymorphism) and restriction analysis in 638 hypertensive patients and 720 normotensive local blood donors in Weisswasser, Germany. Severity of hypertension was estimated by the number of antihypertensive drugs used.

Results

No difference was observed in the allele frequencies and genotype distributions of ACE gene polymorphisms between the two groups, whereas AGT TT homozygotes were more frequent in controls (4.6% vs. 2.7%, P =.08). This became significant (p = 0.035) in women only. AGT TT genotype was associated with a 48% decrease in the risk of having hypertension (odds ratio: 0.52; 95% CI, 0.28 to 0.96), and this risk decreased more significantly in women (odds ratio: 0.28; 95% CI, 0.1 to 0.78). The meta-analysis showed a pooled odds ratio for hypertension of 1.21 (TT vs. MM, 95% CI: 1.11 to 1.32) in Caucasians. No correlation was found between severity of hypertension and a specific genotype.

Conclusion

The ACE I/D polymorphism does not contribute to the presence and severity of essential hypertension, while the AGT M235T TT genotype confers a significantly decreased risk for the development of hypertension in the population studied here. This contrasts to the findings of meta-analyses, whereby the T allele is associated with increased risk for hypertension.     

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 two angiotensinogen gene polymorphisms,M235T and G(-6)A,with chronic heart failure

The aim of the study was to focus on the relationship between the angiotensinogen (AGT) gene polymorphisms, M235T and promoter G(-6)A, and chronic heart failure in the Czech population. A total of 158 patients with chronic heart failure (functional class NYHA II-IV, ejection fraction <40%, cardiothoracic index >50%) were compared with a control group of 200 subjects of similar age and sex distribution, without any personal history of cardiovascular diseases. The AGT gene polymorphisms were detected by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. No significant differences in distributions of AGT genotypes between patients with chronic heart failure (CHF) and controls were found. The differences in distributions of alleles in AGT M235T (P(a)=0.02) and genotypes in AGT G(-6)A (P(g)=0.017) were found within women groups. Within CHF patients the distribution of AGT G(-6)A genotypes was not consistent with Hardy-Weinberg equilibrium (P=0.0001). We found significant relative risk of CHF in the GGMT genotype, OR=2.63 with 95% CI 1.39-4.95, P(corr)=0.01 (in the male group OR=1.83, 95% CI 0.92-3.66, P(corr)=0.3; in the female group OR=15.5, 95% CI 1.86-129.42, P(corr)=0.008). We provide evidence of increased risk in subjects with the GGMT variant of associated genotype of AGT gene for CHF, especially of fifteen-fold risk of this variant in women.     

ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS.

The intrapulmonary renin-angiotensin system via tissue concentration of angiotensin II or bradykinin may have multiple effects on pulmonary pathophysiology. Therefore, it was investigated whether the presence of the D allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism or the A allele of angiotensinogen (AGT) promoter polymorphism (-6)A/G are independent risk factors for 30-day survival in acute respiratory distress syndrome (ARDS) patients. In a prospective study, adults (Germans of Caucasian ethnicity) with ARDS (n = 84) were recruited from the current authors' intensive care unit and genotyped for the ACE I/D and the AGT (-6)A/G polymorphisms, as were 200 healthy Caucasian controls. Mortality was increased in the ACE DD genotype compared with the I allele, and the ACE I/D polymorphism was an independent prognostic factor for 30-day survival. Patients with a homozygous DD genotype were at highest risk for death (hazard ratio 5.7; 95% confidence interval 1.7-19.2) compared with the II genotype. In contrast, the AGT (-6)A/G polymorphism was neither associated with an increased risk for development of ARDS nor with outcome. In patients with acute respiratory distress syndrome, the angiotensin-converting enzyme insertion/deletion polymorphism but not the angiotensinogen (-6)A/G promoter polymorphism is an independent risk factor with a pronounced effect on 30-day survival.     

Angiotensinogen gene M235T polymorphism predicts left ventricular hypertrophy in endurance athletes.

OBJECTIVES: We studied whether left ventricular mass in athletes associates with polymorphisms in genes encoding components of the renin-angiotensin system. BACKGROUND: Adaptive left ventricular hypertrophy is a feature of the athlete's heart. However, similarly training athletes develop left ventricular mass to a different extent, suggesting that genetic factors may modulate heart size. METHODS: We measured left ventricular mass by echocardiography in 50 male and 30 female elite endurance athletes aged 25 +/- 4 (mean +/- SD) years. Deoxyribonucleic acid samples were prepared for genotyping of angiotensinogen (AGT) gene M235T polymorphism, angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and angiotensin II type 1 receptor (AT1) gene A1166C polymorphism. RESULTS: The AGT gene M235T genotypes were significantly associated with left ventricular mass independently of blood pressure in both genders (p = 0.0036 for pooled data). TT homozygotes had greater mass compared with MM homozygotes in both men (147 +/- 12 g/m vs. 132 +/- 15 g/m, p = 0.032) and women (121 +/- 12 g/m vs. 101 +/- 13 g/m, p = 0.019). There was a gender difference in the relation between myocardial mass and AGT genotype, MT heterozygotes resembling MM homozygotes among women and TT homozygotes among men. The other studied gene polymorphisms were not associated with left ventricular mass. CONCLUSIONS: Angiotensinogen gene M235T polymorphism is associated with the variability in left ventricular hypertrophy induced by endurance training, with athletes homozygous for the T allele having the largest hearts. We found no association between ACE gene I/D or AT1 gene A1166C polymorphisms and left ventricular mass.     

Left ventricular mass, carotid wall thickness, and angiotensinogen gene polymorphism in patients with hypertension.

A missense gene mutation with methione-to-threonine amino acid substitution at codon 235 (M235T) of angiotensinogen (AGT) has been associated with higher plasma AGT levels and may influence the pathogenesis of cardiac hypertrophy and atherosclerosis. This study was undertaken to investigate the relationship of the M235T polymorphism of the AGT gene with left ventricular mass (LVM) and carotid intima-media thickness (IMT) in 175 Chinese patients with hypertension. The M235T mutation was detected by a mispairing primer method to create a BstUI restriction site in the polymerase chain reaction. The LVM was calculated with M-mode echocardiographic measures of the left ventricle. The IMT was measured in the common carotid and carotid bifurcation by B-mode ultrasound. Patients with the TT genotype (n = 106) were found to have significantly greater LVM index than those with the MM (n = 32) and MT (n = 37) genotypes (129.2 +/- 34.3 v 112.5 +/- 38.3 and 107.4 +/- 30.0 g/m2, P = .002), but the carotid IMT showed insignificant differences among three genotypic groups (1.320 +/- 0.703, 1.349 +/- 0.777, and 1.309 +/- 0.797 mm, P = .97). The M235T polymorphism (P = .004) was a significant predictor for LVM on multiple regression analysis, controlling all the potential confounding factors including age (P = .04), gender (P = .000), body mass index (P = .000), and so on, but the carotid IMT correlated only with age (P = .000), smoking (P = .02), and tissue plasminogen activator antigen (P = .02). These results indicated that the TT genotype of the AGT gene could be considered a risk factor for the development of cardiac hypertrophy, but not for carotid atherosclerosis in the hypertensive population.     

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.     

An interaction between systolic blood pressure and angiotensin-converting enzyme gene polymorphism on carotid atherosclerosis.

The insertion/deletion (I/D) polymorphism of the human angiotensin-converting enzyme (ACE) gene is a major determinant of circulating ACE activity, with the D allele being associated with higher ACE levels than the I allele. Thus, chronic exposure to high levels of circulating and tissue ACE may well predispose to vascular wall thickening and atherosclerosis. However, the effect of the ACE gene on carotid atherosclerosis remains controversial. We investigated the association between ACE gene I/D polymorphism and risk factor-dependent augmentation of carotid arterial remodeling in subjects with several risk factors for atherosclerosis. We evaluated sclerotic lesions of the common carotid artery with intima-media thickness (IMT) by ultrasonography in 184 patients (mean age +/- SD, 67 +/- 14 years old) and studied whether any risk factor-gene interactions were associated with carotid atherosclerosis. Out of the 184 subjects, 71 had the ACE II genotype, 87 the ID genotype and 26 the DD genotype. There was no significant difference in IMT among the three ACE genotypes. In total subjects, multiple regression analysis showed that age, total-cholesterol (T-C), and HDL-cholesterol (HDL-C) were significantly associated with IMT. However, the association between risk factors and IMT was genotype-specific. Systolic blood pressure (SBP) and HDL-C were significantly associated with IMT in ACE D carriers (DD+ID), but not in subjects with the ACE II genotype. Similarly, T-C was significantly associated with IMT only in subjects with the ACE II genotype. A general linear model of the interaction between the ACE genotype and the conventional risk factors showed that the SBP-ACE genotype interaction were significantly associated with IMT (F = 7.915; p = 0.005). This finding further supports the idea that analysis of risk factor-gene interaction could be a useful tool for deriving specific predictive information about the development of atherosclerosis.     

Association of angiotensinogen M235T and A(-6)G gene polymorphisms with coronary heart disease with independence of essential hypertension: the PROCAGENE study. Prospective Cardiac Gene

OBJECTIVES: We examined the relationship between the angiotensinogen (AGT) gene M235T polymorphism, the variant promoter of the AGT gene A(-6)G and the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and coronary heart disease (CHD) in native Gran Canaria Island habitants, who have the highest rates of CHD in Spain. BACKGROUND: Some studies subject that the ACE (I/D) polymorphism could be associated with CHD, while AGT (M235T) has been related to essential hypertension. METHODS: We studied 304 subjects with angiographic evidence of coronary artery disease and a clinical diagnosis of myocardial infarction or unstable angina and 315 age- and gender-matched controls. Blood was drawn and DNA extracted. Angiotensin-converting enzyme (I/D) gene polymorphism was analyzed by polymerase chain reaction (PCR) and AGT gene polymorphisms by restriction fragment length polymorphism-PCR and mutagenically-separated PCR. RESULTS: The ACE (I/D) polymorphism showed no association with CHD, whereas the frequency distribution of AGT (M235T) genotypes among patients and controls (235T: 29.1% and 19.0%; M235T: 48.5% and 50.2%; M235: 22.4% and 30.8%, respectively) was statistically different (p = 0.005) and not related to the presence of essential hypertension. Similar results were observed with the AGT A(-6)G polymorphism. In multiple logistic regression analysis, CHD odds ratio associated with 235T and M235 homozygotes were 1.7 (1.1 to 2.6) and 0.54 (0.36 to 0.82), respectively. CONCLUSIONS: This study shows that genetic variation of the AGT (M235T), but not the ACE (I/D), genotypes contributes to the presence of CHD independently of blood pressure profile in a subset of the Spanish population with a high prevalence of cardiovascular disease.     

Insertion/deletion polymorphism of angiotensin converting enzyme gene in Korean hypertensive adolescents

The essential role of the renin-angiotensin system (RAS) in controlling blood pressure has been well established. Genes encoding components of the RAS have been proposed as candidate genes that determine genetic predisposition to hypertension and the risk of developing cardiovascular complications. The purpose of this study was to analyze angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms in Korean hypertensive adolescents, and to determine the association between ACE genotype and cardiovascular risk. Forty hypertensive adolescents (16–17 years old, systolic blood pressure (BP) ≥140 mm Hg and/or diastolic BP ≥90 mm Hg) and a control group of twenty normotensive adolescents were included in the study. Obesity index (OI) and body mass index (BMI) were calculated. Skin fold thickness and arm circumference were also measured. Fat mass and fat distribution were analyzed by bioelectrical impedance. Blood pressure was measured at resting state by oscillometric methods. Serum aldosterone, renin, insulin, ACE, homocysteine, vitamin B12, and folate levels were evaluated after a fasting period of 12 h. The carotid intima-media thickness (IMT) and carotid artery diameter were measured by carotid ultrasound. Pulse wave velocity (PWV) and ankle-brachial index (ABI) were also measured. Polymerase chain reaction (PCR) was conducted to amplify DNA from blood samples of each individuals to analyze ACE I/D polymorphism. Genotype frequencies of I/I were 37.5%, I/D 45.0% and D/D 17.5%. Serum ACE levels were 33.5 ± 8.7 U/l in I/I genotype, 48.6 ± 19.8 U/l in I/D genotype and 61.4 ± 22.7 U/l in D/D genotype, which showed that ACE levels were significantly higher in those with D/D or I/D genotype than in I/I genotype. Carotid IMT was significantly greater in D/D group than in I/I group. In conclusion, the D allele is associated with the increased level of ACE in Korean hypertensive adolescents.