Renin-angiotensin system polymorphisms in relation to hypertension status and obesity in a Tunisian population

Essential hypertension (HTA) is the clinical expression of a disordered interaction between the genetic, physiological, and biochemical systems that under usual conditions maintain cardiovascular homeostasis. We studied the effects of the angiotensinogen M235T, angiotensin converting enzyme insertion/deletion (ACE I/D), and angiotensin II receptor 1 (AT1R) A1166C gene polymorphisms on the risk of HTA and to evaluate the relationship between these polymorphisms and obesity. We performed AGT, ACE and AGTR genotyping in 142 hypertensive patients and 191 control subjects using PCR-RFLP methods and PCR, respectively. The three polymorphisms were significantly associated with HTA. Individuals carrying the mutated TT of AGT, DD of ACE and CC of AT1R genotypes had an 1.67 (P = 0.032), 3.09 (P < 0.001) and 3.45 (P < 0.001)-fold increased risk of HTA. After adjustment for sex, smoking, diabetes, dyslipidemia, BMI, triglycerides and DD, TT and CC genotypes, BMI was independent risk factor of HTA (OR = 3.14; P < 0.001). An association of BMI with ACE gene polymorphism (P = 0.035), whereas no association with AGT and AT1R gene polymorphisms was obtained. The proportion of hypertensives is as high as 21.8 and 13.4% in the overweight and the obese DD group. The present study implies that the genotyping for the variants of RAS gene could in the future become an important part of the clinical process of risk identification for HTA.     

Angiotensinogen,angiotensine converting enzyme and plasminogen activator inhibitor-1 gene polymorphism in chronic allograft dysfunction

Despite dramatic improvements in first-year patient and graft survival rates, chronic allograft dysfunction (CAD) remains the leading cause of late renal allograft loss, while current immunologic strategies have little effect on this condition. The renin–angiotensin system (RAS) plays an important role in progression of chronic renal disease. It was shown that plasminogen activator inhibitor-1 (PAI-1) functions in the RAS. This study investigates the possible links between angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE) and PAI-1 genotypes with CAD. Assessments of polymorphism were performed in 127 renal allograft recipients (77 with CAD and 50 with normal renal function). Fifty healthy subjects were also considered for comparison. Genotypes were determined using polymerase chain reaction (PCR) sequence-specific primers and PCR followed by restriction fragment length polymorphism analysis. Kidney recipients with CAD had significantly higher frequencies of the TT than the recipients without CAD (P < 0.05). The transplant recipients with CAD also had significantly higher frequencies of the DD genotype than those without CAD (P < 0.05). No significant differences were observed between the allelic and genotypic distributions of PAI-1 polymorphisms. Therefore, determination of AGT M235T and ACE genotypes prior to transplantation may be useful to identify patients who are at risk for chronic renal transplant dysfunction.     

Angiotensin converting enzyme I/D,angiotensinogen M235T and AT1-R A/C1166 gene polymorphisms in patients with acromegaly

Acromegaly is associated with increased morbidity and mortality related to cardiovascular disease. Hypertension is one of the most common cardiovascular risk factors in acromegalic patients. The aim of this study was to investigate association between the frequencies of angiotensin converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and the angiotensin II type 1 receptor (AT1-R) A/C1166 gene polymorphisms and some clinical parameters of acromegalic patients. Total of 33 acromegalic patients and 63 controls were enrolled to study. We determined the ACE I/D, AGT M235T and AT1-R A/C1166 gene polymorphisms. Serum insulin, glucose, triglyceride, HDL-cholesterol, LDL-cholesterol, growth hormone and Insulin-like growth factor I (IGF-I) levels of subjects were analyzed. The frequencies of ACE and M235T AGT genotype were not significantly different between control and patients. The distribution of AT1R A/C1166 genotypes was significantly different between patients and control subjects (P = 0.016). None of the three ACE genotypes, DD, ID and II displayed significant difference in acromegalic patients. A significant difference in systolic blood pressure and the serum IGF-I levels among the three AGT genotype, MM, MT and TT genotypes was found in patient group. Individuals with MT genotypes had significantly higher serum IGF-I levels and systolic blood pressure than MM and TT genotype subjects, P < 0.05. In addition, serum triglyceride and HDL levels differed significantly between MM and MT genotypes, P < 0.05. However, systolic blood pressure of patients with CC genotypes was found to be significantly higher than AA genotypes individuals in acromegaly group, P < 0.05. It can be said that the angiotensinojen MT and AT1R CC1166 genotype carriers may have more risk than other genotypes in the development of hypertension in acromegaly.     

Association of endothelial nitric oxide synthase gene polymorphisms with classical risk factors in development of premature coronary artery disease

Genetic polymorphism of the endothelial nitric oxide synthase (eNOS) affects the pathogenesis of atherosclerosis and associated with premature coronary artery disease (PCAD). We aimed to explore the association between Glu298Asp polymorphism of the eNOS gene and premature CAD in Egyptians, and the possible interaction between this polymorphism and other risk factors. The study population consisted of 116 patients with PCAD, and 119 controls. Glu298Asp polymorphism (rs1799983) of the eNOS gene was analyzed by polymerase chain reaction (PCR). We found that the TT genotype of the eNOS gene increased the risk of PCAD by 2.6. Hypertension, diabetes, smoking, total cholesterol, triglycerides, LDLc, HDLc and TT genotype of the eNOS gene were independent risk factors for the development of PCAD. We conclude that, the TT genotype of Glu298Asp polymorphism of eNOS gene is an independent risk factor of PCAD in Egyptians. The association of smoking, obesity, dyslipidemia and/or metabolic syndrome with the TT genotype increased the risk of the development of PCAD.     

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

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

AGT M235T and ACE ID polymorphisms and exercise blood pressure in the HERITAGE Family Study

We investigated the association between angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) gene polymorphisms and exercise training responses of resting and exercise blood pressure (BP). BP at rest and during submaximal (50 watts) and maximal exercise tests was measured before and after 20 wk of endurance training in 476 sedentary normotensive Caucasian subjects from 99 families. AGT M235T and ACE insertion/deletion polymorphisms were typed with PCR-based methods. Men carrying the AGT MM and MT genotypes showed 3. 7 +/- 0.6 and 3.2 +/- 0.5 (SE) mmHg reductions, respectively, in diastolic BP at 50 watts (DBP(50)), whereas, in the TT homozygotes, the decrease was 0.4 +/- 1.0 mmHg (P = 0.016 for trend, adjusted for age, body mass index, and baseline DBP(50)). Men with the ACE DD genotype showed a slightly greater decrease in DBP(50) (4.4 +/- 0.6 mmHg) than the II and ID genotypes (2.8 +/- 0.7 and 2.4 +/- 0.5 mmHg, respectively, P = 0.050). Furthermore, a significant (P = 0.022) interaction effect between the AGT and ACE genes was noted for DBP(50); the AGT TT homozygotes carrying the ACE D allele showed no response to training. Men with the AGT TT genotype had greater (P = 0.007) diastolic BP (DBP) response to acute maximal exercise at baseline. However, the difference disappeared after the training period. No associations were found in women. These data suggest that, in men, the genetic variation in the AGT locus modifies the responsiveness of submaximal exercise DBP to endurance training, and interactions between the AGT and ACE loci can alter this response.     

Angiotensinogen and angiotensin-I converting enzyme gene polymorphisms and the risk of coronary artery disease in Chinese

The homozygous deletion allele (DD) of the angiotensin-I converting enzyme (ACE) gene and the T235 homozygote of the angiotensinogen (AGT) gene have been reported to be correlated with an increased prevalence of coronary artery disease (CAD) and myocardial infarction (MI). The importance of the DD genotype and T235 homozygote as genetic risk factors for CAD in Chinese remains uncertain. This study included 426 patients who underwent coronary angiography and 180 healthy subjects without clinical evidence of CAD. Coronary angiography identified 268 patients with CAD (CAD group) and 158 patients without CAD. The healthy subjects and patients without angiographic evidence of CAD constituted the control group. Three polymorphisms were studied: an insertion/deletion (I/D) polymorphism of the ACE gene and the T174 M and M235T polymorphisms of the AGT gene. No association was found between any of the three studied polymorphisms and the risk of CAD or MI in Chinese using univariate or multivariate analysis. In multivariate analysis, the relative risks were 1.20 (95% confidence interval = 0.91–1.61, P = 0.20) for the DD genotype, 1.05 (95% CI = 0.82–1.35, P = 0.69) for the T174 homozygote, and 1.19 (95% CI = 0.91–1.55, P = 0.20) for the T235 homozygote. Similarly, no significant difference was found in the frequencies of the DD genotype and the T174 and T235 homozygotes between the control group, the CAD group, the non-MI group, and the MI group when analyzed according to sex, age, or degree of risk. Our data suggest that neither the DD genotype of the ACE I/D polymorphism nor the T174 and T235 homozygotes of the AGT gene confer significant risk for CAD or MI in Chinese. Received: 18 December 1996 / Accepted: 27 February 1997     

Association between the NOS3 (-786 T/C) and the ACE (I/D) DNA genotypes and early coronary artery disease.

DNA polymorphisms at the endothelium constitutive nitric oxide synthase gene (NOS3) have been linked to the risk of developing coronary artery disease (CAD). In vitro, a polymorphism in the 5' region of the NOS3 gene (-786 T/C) influences promoter activity. This polymorphism has been associated with coronary spasms among Japanese. The genetic variation at the angiotensin-converting enzyme (ACE) is associated with plasma ACE activities and has also been linked with susceptibility to cardiovascular disease. Our objective was to determine if DNA polymorphisms in the NOS3 and ACE genes were associated with early CAD. We analyzed the -786 T/C polymorphism in the 5' flanking region and the 27-bp repeat polymorphism in NOS3 intron 4, as well as the ACE-I/D polymorphism. A total of 170 male smokers (CAD patients) younger than 50 years and 300 male smokers (healthy controls) were genotyped. Frequencies were compared by the chi(2) test, and odds ratios (ORs) and their 95% confidence intervals (CI) were also calculated. Only the -786 T/C polymorphism in the 5' flanking region of the NOS3 gene was significantly associated with early CAD in our population. The frequency of the CC genotype was significantly increased (P = 0.039) in patients compared to controls (OR = 1.67; 95% CI = 1.01, 2.72). We found a synergistic effect between the NOS3-CC and the ACE-DD genotypes in the risk of developing early CAD. The frequency of CC + DD was significantly increased among patients (P = 0.002). Thus, those with a NOS3-CC and an ACE-DD genotype would have a significantly increased risk of suffering an early episode of coronary artery disease (OR = 2.82; 95% CI = 1.40, 5.70). Although based on a limited number of patients, our work suggests that individuals who are NOS3-CC + ACE-DD are at a higher risk for early CAD, probably as a consequence of increased endothelial dysfunction.     

Genetic polymorphisms of the renin-angiotensin system and angiographic extent and severity of coronary artery disease: the CORGENE study

Genetic polymorphisms of the renin-angiotensin system (RAS) have been associated with coronary artery disease (CAD) but no relation between these polymorphisms and coronary atherosclerosis has yet been systematically evaluated. The CORGENE study is a cross-sectional study involving 463 Caucasians who underwent standardized coronary angiography for established or suspected CAD [156 patients with a previous myocardial infarction (MI), 307 without MI]. Four angiographic scores assessing the extent and severity of the coronary lesions were obtained from a double visual analysis of each angiogram, arbitration being achieved by a quantitative measurement. Three different genotypes were analyzed: the angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism, the Met to Thr change at position 235 of the angiotensinogen gene (AGT M235T) and the A to C transition at position 1166 of the angiotensin II type-1 receptor gene (AT1R A1166C). No significant association was observed between these polymorphisms and the clinical characteristics of MI and non-MI subjects. While most classical risk factors were positively correlated with the angiographic scores, no significant relationship could be established with the three genotypes (r ranging from –0.08 to 0.05). Only one significant correlation was observed: between the presence of the AGT 235T allele and the extent of the coronary lesions (r = –0.19, P = 0.04) in patients with low-risk status. These overall results are not in favor of a role of these RAS genetic polymorphisms in the development of coronary atherosclerosis. Received: 23 April 1996 / Revised: 5 August 1996     

Carrier-state of D allele in ACE gene insertion/deletion polymorphism is associated with coronary artery disease,in contrast to the C677-->T transition in the MTHFR gene

Angiotensin I-converting enzyme (ACE), which plays an important role in blood pressure regulation, and methylenetetrahydrofolate reductase (MTHFR) involved in homocysteine metabolism belong to a large group of polypeptides which may be potential risk factors for atherosclerosis and coronary artery disease (CAD). To assess whether polymorphisms of the genes encoding these peptides are associated with CAD in Silesian we conducted a study among 68 individuals suffering from CAD (including 52 cases after myocardial infarction), 51 subjects with positive family history of CAD and 111 controls. We analysed the distribution of genotypes and allele frequencies of the insertion/deletion (I/D) polymorphism in the ACE gene using PCR amplification, and the C677-->T polymorphism in the MTHFR gene using PCR-RFLP analysis. We found that D allele frequency was significantly higher in CAD patients (61%) than in controls (43%) (P = 0.001, OR = 2.06). The D allele carriers (DD + ID genotypes) were more frequent in the CAD patients (85%) compared to control group (65%) (P = 0.003, OR = 3.14), whereas the familial CAD risk group shows the highest frequency of the ID genotype (57% vs 43% in controls). In contrast, the MTHFR polymorphism does not seem to be associated with the disease. Our data indicate that in Silesian CAD patients the disease is strongly associated with carrier-state of the ACE D allele, but not with the C677-->T transition in the MTHFR gene.     

Association of angiotensin II type I and type II receptor genes polymorphisms with the presence of premature coronary disease and metabolic syndrome

Premature coronary artery disease (PCAD) is known to have a particularly strong genetic component. We aimed to investigate the association between angiotensin II receptor type 1 (ATR₁) or type II (ATR₂) genes polymorphisms and PCAD with or without metabolic syndrome in males. 132 male patients with PCAD and 132 controls were included in the study. ATR₁ and ATR₂ genes polymorphisms were analyzed by polymerase chain reaction. The present study revealed that ATR₁ CC genotype and ATR₂ G allele increased the risk of PCAD by 2.9 and 1.3 respectively as well as they increased susceptibility to metabolic syndrome by 4.5 and 2.3 respectively. The present study proved that diabetes, smoking, obesity, total cholesterol, triglycerides, LDLc and HDLc were independent risk factors for the development of PCAD. We concluded that ATR₁ CC genotype and ATR₂ G allele increased the susceptibility of Egyptian males to have PCAD. The increased susceptibility to have metabolic syndrome could be one of the mechanisms leading to the development of PCAD in subjects carrying one or both of these polymorphisms.     

The relationship of the ESR1 gene polymorphisms with the presence of coronary artery disease determined by coronary angiography

Effects of estrogen on the cardiovascular system, mediated mainly by estrogen receptor type alpha (ER alpha), have been well-defined and specific polymorphisms in the ER alpha gene (ESR1) have been associated with several coronary heart diseases including coronary artery disease (CAD) in studies covering different populations. In the present study, we aimed to investigate whether there is an association between two of the known polymorphisms in the ESR1, named c.454-397T>C and c.454-351A>G, and CAD in a Turkish population. One hundred sixty eight patients with CAD and 99 patients without CAD were included in the study. The ESR1 c.454-397T>C and c.454-351A>G polymorphisms were studied by the conventional polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. While no association was found between the c.454-351A>G polymorphism and CAD, the c.454-397T>C genotype distributions were statistically significant independent of known risk factors between CAD-positive (CAD+) and CAD-negative (CAD-) groups (p = 0.001). TT genotype was more frequent in CAD- group than in CAD+ group, 22.2% and 4.8%, respectively. CC genotype was associated with increased risk of CAD (p = 0.001) compared to the TT genotype. When comparing the distribution of CC + TC genotypes to that of TT genotype in CAD+ and CAD- groups, the frequency of CC + TC genotypes showed a significant increase independent of known CAD risk factors in CAD+ subjects (p = 0.001). As a conclusion, a statistically significant relationship between the ESR1 c.454-397T>C polymorphism and CAD were found independent of known CAD risk factors in a Turkish population.     

Insertion/deletion polymorphism of angiotensin-converting enzyme gene--risk factor for coronary artery disease in the Tuzla region population (Bosnia and Herzegovina)

Angiotensin II is the major effector molecule of renin-angiotensin system; its production can be conveniently interrupted by angiotensin-converting enzyme (ACE). Typical plasma levels of ACE accompany the I/D polymorphism; however, a controversy exists as to whether the DD genotype of the ACE polymorphism affects the risk for the development of coronary artery disease (CAD) and to what extent the ACE polymorphism is associated with CAD in different populations. We compared the I/D polymorphism in 212 CAD patients younger than 50 years with 165 healthy control individuals. They were all from the Tuzla region in Bosnia and Herzegovina. Patients with CAD had a higher prevalence of the DD genotype (36.3%) than controls (25.6%). The odds ratio for the ACE DD genotype in CAD patients was 1.7 (95% confidence interval 1.0-2.7; p < 0.05). We may conclude that the D/D genotype of the ACE gene polymorphism is associated with an increased risk for CAD in the Bosnian population.     

ACACβ gene (rs2268388) and AGTR1 gene (rs5186) polymorphism and the risk of nephropathy in Asian Indian patients with type 2 diabetes

Patients with type 2 diabetes (T2DM) are usually obese and concurrent obesity results into activation of the renin–angiotensin-system (RAS) which is a risk factor for diabetic nephropathy (DN). Gene–gene interaction between acetyl-coenzymeA carboxylase beta (ACACβ) gene, which is involved in fatty acid metabolism and angiotensin II receptors (AGTR1) gene, which mediates RAS proteins actions on renal tissue, polymorphism with DN have not been studied earlier. The present study was designed with the aim to examine the association of an ACACβ (rs2268388) and AGTR1 (rs5186) gene polymorphism with the risk of DN in Asian Indians. 1,158 patients with T2DM belonging to two independently ascertained North Indian and one South Indian cohorts were genotyped for ACACβ (rs2268388) and AGTR1 (rs5186) polymorphism using real time PCR-based Taq-man assay and PCR–RFLP assays. In all the three cohorts, a significantly higher frequency of T allele and TT genotypes of ACACβ and C allele and CC genotypes of AGTR1 were found in patients with DN as compared to patients without nephropathy. Further, T allele of ACACβ and C allele of AGTR1 were found to be significantly associated with proteinuria, a hallmark of DN. We also found significant epistatic interactions between these two genes. TT genotypes of ACACβ gene and CC genotype of AGTR1 gene confers the risk of DN and both genes had significant epistatic interaction in Asian Indian patients with T2DM.     

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

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

Gender specificity of a genetic variant of angiotensin-converting enzyme and risk of coronary artery disease

Etiological factors for coronary artery disease (CAD) involve a wide range of gene and environmental interactions. One of the systems being implicated in the pathophysiology of CAD is the renin-angiotensin system (RAS). However, the genetic polymorphisms of this system have not been widely studied in Iranian patients diagnosed with CAD. The aim of this study was to assess the relationship between six gene polymorphisms of RAS components and CAD in a sample of Iranian population. A total of 374 participants were enrolled in a case/control study. The presence of CAD was determined by coronary angiography. Genotyping of six RAS gene polymorphisms was performed using a modified PCR–RFLP method. Our results revealed, for the first time, a significant independent association of angiotensin-converting enzyme (ACE) A-240T polymorphism and incidence of CAD among Iranian women (P = 0.005, OR = 20.4, 95 % CI = 2.49–41.2). There has also been a significant difference in genotype distribution of ACE A-240T (P = 0.008) and angiotensin II receptor type 2 C3123A polymorphism (P = 0.032) in Iranian female participants. In conclusion, TT genotype of ACE A-240T seems to be a genetic risk factor for CAD in Iranian women.     

Polymorphisms of EDNRB, ATG, and ACE genes in salt-sensitive hypertension

Almost 50% of hypertensive individuals manifest blood pressure changes in response to salt depletion or repletion and are termed "salt sensitive" (SS). Blunted activity of the endothelin (ET) system and the renin-angiotensin-aldosterone system (RAAS) have been reported as possible mechanisms contributing to salt sensitivity. Data are available that endothelin receptor subtype B (ETBR)-deficient rats develop salt-sensitive hypertension when fed a high-salt diet. Whether the ETBR gene (EDNRB) is involved in genetic predisposition to human salt-sensitive hypertension has not been studied so far. We screened EDNRB in 104 hypertensive patients (49 salt sensitive and 55 salt resistant) and 110 normotensive controls. No new sequence variation was found, but genotype distribution of the common polymorphism G1065A revealed that the AA + GA genotypes were significantly more frequent in salt-resistant than in salt-sensitive individuals (p = 0.007), suggesting a protective role for the A allele. We also screened angiotensinogen gene AGT M235T and angiotensin-converting enzyme insertion/deletion polymorphism ACE I/D and found an association between TT genotype and hypertension. A possible synergistic effect to salt-sensitive hypertension was found by combining EDNRB GG with ACE DD/ID genotypes. In conclusion, our data confirm the role of ET system and RAAS in salt-sensitive hypertension.     

C677T mutation of methylenetetrahydrofolate reductase gene and serum homocysteine levels in Turkish patients with coronary artery disease

Elevated levels of homocysteine is a risk factor for coronary artery disease. The C677T transition in methylenetetrahydrofolate reductase (MTHFR) is associated with increased homocysteine levels in the general population. We analysed the association between the MTHFR C677T polymorphism and serum homocysteine concentrations in patients with coronary artery disease (CAD). Allele frequencies for the 'C' (wild-type) and 'T' alleles were 0.71 and 0.29 in CAD patients and 0.70 and 0.30 in controls, respectively. There was no difference in the distribution of MTHFR genotypes between patients with CAD and control subjects (p > 0.05). In the patient group, homocysteine levels were higher than controls but not significantly (13.99 +/- 7.44 vs. 11.77 +/- 5.18 micromol l(-1); p > 0.05). Serum homocysteine concentration was significantly higher in the TT genotype with respect to CC and CT genotypes in both the control group (p < 0.01) and patient group (p < 0.01). Systolic and diastolic blood pressures in subjects with different MTHFR genotypes did not differ significantly. In conclusion, MTHFR C677T mutation was significantly related to hyperhomocysteinemia. In spite of the clear effect of the MTHFR polymorphism on elevated homocysteine levels, we did not observe any associations among the MTHFR genotypes with a the risk of CAD in the Turkish population.     

Synergism between paraoxonase Arg 192 and the angiotensin converting enzyme D allele is associated with severity of coronary artery disease

We have previously shown that angiotensin-converting enzyme (ACE) gene D allele is an independent risk factor for early onset coronary artery disease (CAD). Little is known about the concomitant presence of the ACE gene D allele and paraoxonase (PON1) codon 192 arginine (Arg) on the severity of CAD. Regarding the high rate of CAD among Iranians the aim of present study was to examine the hypothesis of synergistic effects between ACE-D and PON1-Arg alleles on predisposition and the severity of CAD in our population. The PON1 192 and ACE insertion/deletion (I/D) genotypes were detected by PCR-RFLP and PCR, respectively in 414 individuals undergoing their first coronary angiography. Patients were placed into one of two groups: CAD and control without CAD or diabetes. We mentioned the synergistic effects of both genes and not ACE gene alone is a risk factor for CAD. We found that PON1 Arg 192 and ACE D allele act synergistically to increase the risk of CAD (OR 1.3, P = 0.044). Our results showed a significant correlation between the possession of both PON1 192 Arg and the ACE D allele and the extent of CAD in CAD patients and CAD subjects without diabetes, represented by the increased frequency of three-vessel disease with OR 2.7, P = 0.046; χ² = 4, P = 0.046 and OR 2.4, P = 0.051; χ² = 3.8, P = 0.051, respectively. We found that PON1 Arg 192 and ACE D alleles act synergistically to increase the risk of CAD in CAD patients and CAD subjects without diabetes from west of Iran, who have high frequency of three-vessel disease. Our data suggest that PON1 192 Arg and the ACE D allele in combination with each other can be important independent risk factor for severity of CAD in patients carrying both PON1 192 Arg and the ACE D allele in a west population of Iran.