Association between -T786C NOS3 polymorphism and resistant hypertension: a prospective cohort study

Background

Autonomic dysfunction appears to play a significant role in the development of atrial fibrillation (AF), and impaired heart rate recovery (HRR) during exercise treadmill testing (ETT) is a known marker for autonomic dysfunction. However, whether impaired HRR is associated with incident AF is unknown. We studied the association of impaired HRR with the development of incident AF, after controlling for demographic and clinical confounders.

Methods

We studied 8236 patients referred for ETT between 2001 and 2004, and without a prior history of AF. Patients were categorized by normal or impaired HRR on ETT. The primary outcome was the development of AF. Cox proportional hazards modeling was used to control for demographic and clinical characteristics. Secondary analyses exploring a continuous relationship between impaired HRR and AF, and exploring interactions between cardiac medication use, HRR, and AF were also conducted.

Results

After adjustment, patients with impaired HRR were more likely to develop AF than patients with normal HRR (HR 1.43, 95% confidence interval (CI) 1.06, 1.93). In addition, there was a linear trend between impaired HRR and AF (HR 1.05 for each decreasing BPM in HRR, 95% CI 0.99, 1.11). No interactions between cardiac medications, HRR, and AF were noted.

Conclusion

Patients with impaired HRR on ETT were more likely to develop new-onset AF, as compared to patients with normal HRR. These findings support the hypothesis that autonomic dysfunction mediates the development of AF, and suggest that interventions known to improve HRR, such as exercise training, may delay or prevent AF.     

Association between ACE I/D polymorphism and pulmonary tuberculosis in Chinese population

Tuberculosis (TB) remains a global public health problem worldwide. The objective of the current study is to investigate the possible association of ACE I/D polymorphism with pulmonary TB (PTB) for Chinese in Sichuan province. Three hundred eighty-six PTB patients and 398 healthy controls were genotyped to analyze the I/D polymorphism using PCR method. The results showed that the I/D polymorphism was not associated with susceptibility to PTB for Chinese (D vs. I: OR 1.03, 95 % CI 0.84–1.26, and P = 0.77; DD vs. II+DI: OR 1.09, 95 % CI 0.73–1.63, and P = 0.68; DD+DI vs. II: OR 1.00, 95 % CI 0.74–1.33, and P = 0.98). The I/D polymorphism in the ACE gene may not a risk factor for PTB in Chinese.     

Association between I/D polymorphism in the ACE gene and sarcoidosis in Turkish patients

Sarcoidosis is a chronic inflammatory disease with a complex pathogenesis and unknown etiology characterized by noncaseating granulomas that invade the lungs, eyes, liver and other organs. Insertion (I)/deletion (D) polymorphism in the gene encoding the angiotensin-converting enzyme (ACE) has been studied to examine the genetic predisposition to sarcoidosis in different populations, but the results have been inconsistent and inconclusive. This study aimed to determine the frequencies of the genotypes and alleles of I/D polymorphism in the ACE gene in Turkish patients as a distinct ethnic group and to investigate whether such polymorphism is associated with predisposition to sarcoidosis. Genomic DNA samples obtained from 154 individuals (70 patients with sarcoidosis and 84 healthy controls) were used in the study. The DNA was amplified using polymerase chain reactions using allele-specific primers. The amplified products were analyzed by 2 % agarose gel electrophoresis followed by UV transillumination. The allele frequencies and genotype distribution of the groups were analyzed using the Chi square test. There were no significant differences between the controls and sarcoidosis cases with respect to genotype distribution (χ² = 4.202, p = 0.122) and allele frequencies (χ² = 1.358, p = 0.244). Our results suggest that I/D polymorphism in the ACE gene does not cause a genetic predisposition to sarcoidosis in Turkish patients.     

Association of AGTR1 (A1166C) and ACE (I/D) Polymorphisms with Breast Cancer Risk in North Indian Population

Renin angiotensin system (RAS) comprising Angiotensin converting enzyme (ACE), Angiotensin II (Ang II) and its receptor Angiotensin II receptor type I (AGTR1), plays a critical role in several diseases including cancer. A single nucleotide polymorphism (SNP) A1166C located in 3′ untranslated region (UTR) of AGTR1 and an insertion/deletion (I/D) polymorphism present in intron 16 of ACE gene have been associated with many diseases, but their association with Breast cancer (BCa) is still debatable. Here, we for the first time investigated the association of these polymorphisms in a North Indian BCa cohort including 161 patients and 152 healthy women. The polymorphisms were evaluated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) respectively. The association between these polymorphisms and BCa risk was estimated by calculating Odds Ratio (OR) and chi-square (χ²) test. The DD genotype/D allele of ACE (I/D) polymorphism and “AC and CC” genotype/C allele of AGTR1 (A1166C) polymorphism were associated with higher risk of BCa when evaluated independently. Furthermore, interaction analysis of “AC and CC” and DD genotype and combination of “C and D” alleles of both polymorphisms revealed significantly greater BCa risk than that observed independently. Conclusively, women harboring “AC or CC” genotype/C allele for AGTR1 (A1166C) polymorphism and DD genotype/D allele for ACE (I/D) polymorphisms have a predisposition to develop more aggressive disease with advanced staging and larger tumor size. Our study indicates importance of genetic screening based on these polymorphisms for women, who may have higher risk of BCa.     

Association of angiotensin converting enzyme (ACE) gene I/D polymorphism and polycystic ovary syndrome (PCOS)

This study was conducted in Turkish patients with polycystic ovary syndrome to determine the frequency of I/D polymorphism genotypes of angiotensin converting enzyme gene, and to examine the role of this polymorphism in polycystic ovary syndrome development. Genomic DNA obtained from 200 persons (100 patients with polycystic ovary syndrome and 100 healthy controls) was used in the study. DNA was multiplied by polymerase chain reaction using I and D allele-specific primers. Polymerase chain reaction products were assessed with a charge coupled device (CCD) camera by being exposed to 2% agarose gel electrophoresis. There was statistically significant difference between the groups with respect to genotype distribution (p < 0.001). The D allele frequency was indicated as 68% and I allele was as 32% in the patients, whereas it was 51.5-48.5% respectively in the control group. As a result of our study we may assert that angiotensin converting enzyme gene I/D polymorphism DD genotype should be considered as a genetic marker in polycystic ovary syndrome development in this Turkish study population.     

Association of GNB3 gene C825T polymorphism with coronary heart disease

The C825T polymorphism in the gene encoding the G protein beta 3 subunit (GNB3) causes enhanced G protein activation and the increased in vitro cell proliferation. We investigated the association of gene GNB3 C825T polymorphism with coronary artery disease (CAD) in the Russian population. A total of 313 patients with CAD diagnosed on the basis of clinical studies and coronary angyography were examined. The control group included 132 individuals that lacked clinical CAD symptoms and had matching profile of coronary artery disease risk factors. Blood pressure was measured using standard protocols. Increased levels of diastolic and systolic pressure was observed in both groups. The allele and genotype frequencies of this polimorphic marker were significantly higher in the CAD patients than in control. We found that the frequency of allele C and genotype CC was significantly higher in the CAD patients (OR = 1.55; P = 0.0079; OR = 1.63; P = 0.0215, respectively), which suggests higher risk of this pathology in carriers of allele C and genotype CC. Thus, in the Russian population coronary artery disease is associated with GNB3 allele C and genotype CC.     

Association of GNB3 gene C825T polymorphism with coronary heart disease

The C825T polymorphism in the gene encoding the G protein beta 3 subunit (GNB3) causes enhanced G protein activation and the increased in vitro cell proliferation. We investigated the association of gene GNB3 C825T polymorphism with coronary artery disease (CAD) in the Russian population. A total of 313 patients with CAD diagnosed on the basis of clinical studies and coronary angyography were examined. The control group included 132 individuals that lacked clinical CAD symptoms and had matching profile of coronary artery disease risk factors. Blood pressure was measured using standard protocols. Increased levels of diastolic and systolic pressure was observed in both groups. The allele and genotype frequencies of this polimorphic marker were significantly higher in the CAD patients than in control. We found that the frequency of allele C and gen-. otype CC was significantly higher in the CAD patients (OR = 1.55; P = 0.0079; OR = 1.63; P = 0.0215, respectively), which suggests higher risk of this pathology in carriers of allele C and genotype CC. Thus, in the Russian population coronary artery disease is associated with GNB3 allele C and genotype CC.     

A haplotype constituted of four MMP-2 promoter polymorphisms (-1575G/A, -1306C/T, -790T/G and -735C/T) is associated with coronary triple-vessel disease.

Vascular lesion development is associated with an accumulation of extracellular matrix proteins within the vessel wall. The proteins are degraded by matrix metalloproteinases (MMPs). There is also evidence indicating a participation of the MMPs in the weakening of atherosclerotic plaque that predisposes to lesion disruption. The aim of the study was to test an association among haplotypes of four single nucleotide MMP-2 promoter polymorphisms and the angiographically confirmed coronary triple-vessel disease (TVD). Incidence of haplotypes of four MMP-2 promoter polymorphisms (-1575G/A, -1306C/T, -790T/G and -735C/T) determined by PCR reactions with restriction analyses in 187 patients with coronary TVD (153 men, 34 women, age median 65 years) was compared to 196 control subjects without clinical signs of coronary heart disease (131 men and 65 women, age median 60 years). The incidence of two similar haplotypes was found to be different between patients and healthy subjects. The haplotype GCTC was more frequent in the TVD patients (P=0.01) though the haplotype GCGC was identified only in healthy subjects (P=0.001). Interestingly, the GCTC is the most frequent polymorphic haplotype composed of four promoter SNPs localized in the MMP-2 gene (53% in healthy subjects vs. 66% in patients with TVD) and the haplotype GCGC is the least frequent polymorphic one (4.4% in healthy subjects vs. 0% in patients with TVD). Two different MMP-2 promoter haplotypes differing only in -790T/G allele are significantly more or less frequent in coronary TVD compared to non-ischemic persons. Thus, the -790T/G MMP-2 genotype might be used as a genetic marker representing MMP-2 promoter variability for the TVD with odds ratio for TT and TG genotypes 2.59, 95% confidential interval 1.21-5.55, P=0.009. The analysis of promoter MMP-2 gene variability could help us to understand individual susceptibility to MMP inhibitor treatment of the coronary artery disease.     

Association between angiotensin-converting enzyme gene polymorphism and coronary artery disease

An insertion/deletion (I/D) polymorphism in the gene for angiotensin-converting enzyme (ACE) is associated with myocardial infarction and other cardiac pathology. There is evidence for a role of the renin-angiotensin system in cell growth and in the repair of damaged arterial walls, so the ACE gene is postulated to be a candidate gene affecting the important clinical problem of coronary artery disease (CAD). In view of the clinical importance of the ACE as a major marker of cardiovascular diseases, we investigated the I/D polymorphism of the ACE gene in Turkish CAD patients in comparison with control subjects to evaluate a possible association between CAD and the gene encoding ACE. Polymerase chain reaction, restriction fragment length polymorphism, and agarose gel electrophoresis techniques were used to determine the ACE genotype in 58 subjects. The frequencies of ACE D and ACE I allele among the patients with CAD were 62.26% and 37.73 % and in the control subjects were 49.3% and 50.76%, respectively. The greater frequency of deletion allele (D) was in the CAD group than in the control subjects was significant (P < 0.01).     

Association between rs10118757(A/G) in methylthioadenosine phosphorylase gene and coronary artery disease in Chinese Hans

Studies focusing on the association of gene methylthioadenosine phosphorylase (MTAP) with the risk of coronary artery disease (CAD) and myocardial infarction (MI) are limited.     

Association of homocysteine and methylene tetrahydrofolate reductase (MTHFR C677T) gene polymorphism with coronary artery disease (CAD) in the population of North India

The implications of the methylene tetrahydrofolate reductase (MTHFR) gene and the level of homocysteine in the pathogenesis of coronary artery disease (CAD) have been extensively studied in various ethnic groups. Our aim was to discover the association of MTHFR (C677T) polymorphism and homocysteine level with CAD in north Indian subjects. The study group consisted of 329 angiographically proven CAD patients, and 331 age and sex matched healthy individuals as controls. MTHFR (C677T) gene polymorphism was detected based on the polymerase chain reaction and restriction digestion with HinfI. Total homocysteine plasma concentration was measured using immunoassay. T allele frequency was found to be significantly higher in patients than in the control group. We found significantly elevated levels of mean homocysteine in the patient group when compared to the control group (p = 0.00). Traditional risk factors such as diabetes, hypertension, smoking habits, a positive family history and lipid profiles (triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol), were found significantly associated through univariate analysis. Furthermore, multivariable logistics regression analysis revealed that CAD is significantly and variably associated with diabetes, hypertension, smoking, triglycerides and HDL-cholesterol. Our findings showed that MTHFR C677T polymorphism and homocysteine levels were associated with coronary artery disease in the selected population.     

Association between interleukin-16 polymorphisms and risk of coronary artery disease

Growing evidence has shown that inflammation plays crucial roles in the development of coronary artery disease (CAD). Interleukin-16 (IL-16), a multifunctional cytokine, is involved in a series of inflammatory disorders. The aim of this study was to investigate the association between IL-16 polymorphisms and risk of CAD. We analyzed two polymorphisms of IL-16 (rs4778889 T/C and rs11556218 T/G) in 157 patients with CAD and 202 healthy controls by using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. The TG/GG genotypes of rs11556218 T/G were associated with a significantly increased risk of CAD as compared with the TT genotype (odds ratio?=?1.77; 95% confidence intervals, 1.16-2.71). This finding indicates that IL-16 may be used as a genetic marker for CAD susceptibility.     

Association between the − 786T>C 1polymorphism in the promoter region of endothelial nitric oxide synthase (eNOS) and risk of coronary artery disease: A systematic review and meta-analysis

Background

A variety of studies have evaluated the association between the − 786T>C polymorphism in the promoter region of endothelial nitric oxide synthase (eNOS) and risk of coronary artery disease (CAD). However, the results remain conflicting. To better understand the role of eNOS − 786T>C polymorphism in CAD risk, we conducted a comprehensive systematic review and meta-analysis.

Methods

Case–control, cohort or cross-sectional studies evaluating the association between eNOS − 786T>C polymorphism and CAD risk were searched in electronic databases of PubMed, ISI Web of Knowledge, Medline, Embase and Google Scholar Search (up to January 2013). Overall and subgroup analyses were performed. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the association between eNOS − 786T>C polymorphism and CAD risk. Statistical analysis was performed with Review Manager 5.0 and STATA12.0.

Results

Twenty-four studies were analyzed between 6192 CAD cases and 9281 healthy controls. The combined results of overall analysis showed significant positive associations between CAD risk and eNOS − 786T>C polymorphism in dominant model (OR = 1.45, 95% CI = 1.27–1.65), recessive model (OR = 1.37, 95% CI = 1.20–1.56), homozygote comparison (OR = 1.64, 95% CI = 1.31–2.04), heterozygote comparison (TC vs. TT, OR = 1.39, 95% CI = 1.23–1.57; CC vs. TC, OR = 1.20, 95% CI = 1.04–1.37) and allele comparison (OR = 1.35, 95% CI = 1.21–1.50). On subgroup analysis based on the ethnicity of population (Caucasians, Asians and others), significant differences were found in all genetic models for Caucasians, similar associations existed in Asians except heterozygote comparison (CC vs. TC). However, the associations were only found in dominant model, heterozygote comparison (TC vs. TT) and allele comparison for the populations named others.

Conclusions

Our investigations demonstrate the significant associations between eNOS − 786C>T polymorphism and CAD risk, and this polymorphism might become an early marker for the risk evaluation of CAD.     

Association of polymorphic marker G(-455)A of gene FGB with coronary artery disease

Patients with coronary artery disease (CAD), including those who have had myocardial infarction (MI), and control subjects have been compared with respect to the distributions of the alleles and genotypes of polymorphic marker G(-455)A of gene FGB encoding the fibrinogen beta-chain. The groups studied do not differ significantly with respect to the distributions of G(-455)A alleles and genotypes. This indicates that this marker is not associated with CAD in the Moscow population. Allele A of the G(-455)A polymorphic marker has been found to be associated with an increased fibrinogen content of blood plasma in women with CAD.     

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.     

Post-hoc analysis on the CD14 C(-260)T promoter polymorphism and coronary heart disease

Functional C(-260)--> T polymorphism in the promoter of the CD14 gene has been reported to be associated with coronary heart disease (CHD). The functional role of the polymorphism, however, is still a matter of debate, since several studies have not proved its effect on clinical outcomes associated with atherosclerosis. Cardiovascular-related morbidity and mortality was assessed in a post-hoc approach four years after baseline characterization of patients (male/female n = 36/32) with angiographically proven coronary heart disease. CD14 C(-260)--> T promoter genotype was determined at baseline. Seventeen out of 20 CHD patients with non-lethal cardiovascular events carried at least one T-allele. CD14 T-260 allele carriers have a 3.59-fold (95 % confidence interval: 1.11-6.75) increased risk for non-lethal cardiovascular events (Kaplan-Meier plot: log rank test p = 0.029). All patients with lethal outcomes (n = 6) were also T-allele carriers. Multivariate logistic regression analysis among CHD patients including age, established risk factors and the C(-260)--> T polymorphism as covariates and non-lethal events as a dependent variable confirmed the independent prospective effect of the T-allele on cardiovascular outcomes in this subset. Further evidence is provided for the role of CD14 C(-260)--> T promoter polymorphism as a genetic susceptibility marker of atherosclerosis in patients with an advanced clinical course of the disease. Due to the small sample size and post-hoc character of the study large-scale prospective studies that monitor patients with proven CHD are needed to confirm these findings.     

The importance of association between angiotensin-converting enzyme (ACE) Gene I/D polymorphism and diabetic peripheral neuropathy

Background

Diabetic peripheral neuropathy (DPN) is a microvascular complication of diabetes mellitus (DM) due to decreasing quality of life. In the present study, it is aimed to evaluate angiotensin-converting enzyme (ACE) Gene I/D polymorphism in Turkish population.

Materials and methods

Two hundred and thirty-five DPN patients and two hundred and eighty-one controls were enrolled in this study. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) analyses for the ACE gene I/D polymorphism.

Results

Baseline characteristics of the DPN patients according to ACE genotypes were similar, except for history of hypertension. The frequency of II genotype was significantly higher in patients with positive history of hypertension than the patients with negative history of hypertension (p = 0.013). DD genotype of I/D polymorphism was found to be a susceptibility factor for DPN in homozygous form (p = 0.032). According to allele frequencies, D allele of I/D polymorphism was found to be a susceptibility factor for DPN (p = 0.031).

Conclusion

ACE gene I/D polymorphism may research in DM patients to determine genetic predisposition for DPN. It can be useful for taking early measures and avoiding DPN in a Turkish population.     

Association between coronary lesion severity and distal microvascular resistance in patients with coronary artery disease

Homogeneity of microvascular resistance in different perfusion areas of the same heart is generally assumed. We investigated the effect of the severity of an epicardial stenosis on microvascular resistance in 27 patients with coronary artery disease and stable angina. All patients had an angiographically normal coronary artery, an artery with an intermediate lesion, and an artery with a severe lesion; the latter was treated with angioplasty. In each patient, distal blood flow velocity and pressure were measured during baseline and maximal hyperemia (induced by intracoronary adenosine) using a Doppler and pressure guide wire, respectively. The ratio of mean distal pressure to average peak blood flow velocity was used as an index for the microvascular resistance (MRv). Within patients, the hyperemic MRv was higher in arteries with more severe stenosis (P = 0.021). After percutaneous transluminal coronary angioplasty (PTCA), the hyperemic MRv decreased (pre-PTCA, 2.6 vs. post-PTCA, 1.9 mmHg.cm(-1)s(-1), P < 0.01) toward the value of the reference artery (1.7 mmHg.cm(-1)s(-1); P = 0.67). We conclude that there is a positive association between coronary lesion severity and variability of distal microvascular resistance that normalizes after angioplasty. This study challenges the concept of uniform distribution of hyperemic MRv that is relevant for the interpretation of both noninvasive and invasive diagnostic tests.     

Association of adiponectin gene functional polymorphisms (-11377C/G and +45T/G) with nonalcoholic fatty liver disease

Adiponectin levels are reduced in NAFLD patients and genetic variants of adiponectin have been frequently associated with type 2 diabetes and insulin resistance. To determine the genotypic frequencies of adiponectin functional polymorphisms (-11377C/G and +45T/G) and their subsequent effect on disease progression and plasma adiponectin levels in the patients with NAFLD. A total of 137 NAFLD patients and 250 matched controls were enrolled in the study. DNA sequencing and genotyping were performed to identify the genetic variants. The plasma adiponectin levels were assessed by ELISA. Homozygous mutant genotype of adiponectin SNPs, -11377C/G and +45T/G, were significantly more prevalent in NAFLD patients than controls (Bonferroni corrected p=0.014 and 0.018, respectively). Plasma adiponectin levels were significantly lower in the NAFLD patients as compared to controls. Moreover, presence of 'G' allele at position -11377C/G and +45T/G was found to be associated with necroinflammatory grade and reduced adiponectin levels, (p values 0.02 and 0.01) respectively. -11377G and +45G alleles are associated with severity of liver disease and hypoadiponectemia, in the patients with NAFLD, respectively.