Serum Metrnl is associated with the presence and severity of coronary artery disease

Meteorin‐like (Metrnl) is a novel adipokine that is highly expressed in white adipose tissue. Metrnl stimulates energy expenditure and improves glucose tolerance in rodents. However, whether Metrnl plays a role in coronary artery disease (CAD) remains to be elucidated. The present study aimed to investigate the association of serum Metrnl with CAD in Chinese patients. A total of 193 patients with CAD and 156 control subjects were enrolled in this study. Serum Metrnl concentration was measured by enzyme‐linked immunosorbent assay. Anthropometric phenotypes, fasting glucose, serum lipids, and inflammatory cytokines were measured. Serum Metrnl was lower in CAD patients when compared to those controls (132.41 vs 173.17 pg/mL, P < 0.001). Serum Metrnl was negatively correlated with metabolic parameters, including body mass index, total cholesterol, and low‐density lipoprotein cholesterol as well as inflammatory markers including high‐sensitivity C‐reactive protein, IL‐1β, and IL‐11 even after adjustment for potential confounding variables (P < 0.05). In multivariable logistic regression analyses, compared to those in the highest tertile of serum Metrnl levels, subjects in the lowest tertile had the highest risks for CAD (adjusted OR = 2.63, 95% CI = 1.46‐4.27, P = 0.001). After adjustment for potential confounding variables, serum Metrnl was also decreased as the number of stenosed vessels increased (P < 0.001). Furthermore, decreased Metrnl level was negatively correlated with the severity of CAD quantified by the Gensini score. This first case‐control study shows significant associations of serum Metrnl with the presence and severity of CAD, suggesting Metrnl might be a new promising therapeutic target for CAD.     

Leucocyte copper, a marker of copper body status is low in coronary artery disease

To elucidate the relationship between leucocyte copper as a reliable, sensitive index of copper body status and extent of atherosclerosis in patients with Coronary Artery Disease (CAD) the present case-control study was carried out. 80 subjects were studied (23 females and 57 males), aged between 30-70, due to have a angiography. Individual angiograms were scored by combining the individual scores in all the major coronary arteries into one score of a scale 1.00 for patency to 0.00 for severe CAD. Serum and leucocyte copper and zinc were determined by GFAAS. No significant difference between patients with advanced CAD and relatively normal arteries were observed in the lipid profile and levels of plasma copper. Leucocyte copper had a significant link with the severity of atherosclerosis which was independent of sex. There was a linear relationship between the degree of decreasing leucocyte copper concentration and angiogram score. These findings give support to the hypothesis that marginal copper status, assessed by decreased leucocyte copper level, is associated with developing CAD.     

Common gene polymorphism in ATP-binding cassette transporter A1 and coronary artery disease: A genetic association study and a structural analysis

ATP-binding cassette transporter A1 (ABCA1) has a crucial role in removing intracellular cholesterol and plays a protective role against atherosclerosis. Therefore, genetic polymorphisms in this gene may alter the susceptibility to coronary artery disease (CAD). This study was aimed to examine the association of rs2230806 (c.1051 G > A; p.R219K) variation in the ABCA1 gene with CAD in a case-control design which was followed by a meta-analysis and in silico approach. In the case-control study, 300 subjects including 150 individuals with CAD and 150 healthy controls were recruited. The c.1051 G > A genotyping was done by polymerase chain reaction-restriction fragment length polymorphism method. In the meta-analysis, eligible studies were collected from PubMed, Google Scholar, and ScienceDirect databases and pooled odds ratio, heterogeneity, publication bias, and sensitivity analyses were carried. Finally, some bioinformatics tools were employed to assess the impacts of p.R219K variation on ABCA1 protein structure. Our case-control examination showed a statistically significant association between c.1051 G > A genetic polymorphism and CAD risk. In addition, the meta-analysis showed reliable significant associations between c.1051 G > A transition and risk of CAD in the Caucasian population. In silico analysis showed that the p.R219K substitution could alter the secondary structure, hydrophobicity pattern, and Ramachandran plot of ABCA1. These findings elucidate that the c.1051 G > A variation could be a genetic risk factor for CAD and it could be considered as a prognostic and predictive biomarker for susceptible individuals.     

ABCA1 gene promoter DNA methylation is associated with HDL particle profile and coronary artery disease in familial hypercholesterolemia

High-density lipoproteins cholesterol (HDL-C) level, a strong coronary artery disease (CAD) clinical biomarker, shows significant interindividual variability. However, the molecular mechanisms involved remain mostly unknown. ATP-binding cassette A1 (ABCA1) catalyzes the cholesterol transfer from peripheral cells to nascent HDL particles. Recently, a differentially methylation region was identified in ABCA1 gene promoter locus, near the first exon. Therefore, we hypothesized that DNA methylation changes at ABCA1 gene locus is one of the molecular mechanisms involved in HDL-C interindividual variability. The study was conducted in familial hypercholesterolemia (FH), a monogenic disorder associated with a high risk of CAD . Ninety-seven FH patients (all p.W66G for the LDLR gene mutation and not under lipid-lowering treatment) were recruited and finely phenotyped for DNA methylation analyses at ABCA1 gene locus. ABCA1 DNA methylation levels were found negatively correlated with circulating HDL-C (r = -0.20; p = 0.05), HDL2-phospholipid levels (r = -0.43; p = 0.04), and with a trend for association with HDL peak particle size (r = -0.38; p = 0.08). ABCA1 DNA methylation levels were also found associated with prior history of CAD (CAD = 40.2% vs. without CAD = 34.3%; p = 0.003). These results suggest that epigenetic changes within the ABCA1 gene promoter contribute to the interindividual variability in plasma HDL-C concentrations and are associated with CAD expression. These findings could change our understanding of the molecular mechanisms involved in the pathophysiological processes leading to CAD.     

Polymorphisms of the uridine-diphosphoglucuronosyltransferase 1A1 gene and coronary artery disease

Bilirubin, an antioxidant in the blood, plays a role in protection from atherosclerosis. The level of bilirubin is highly correlated to the incidence of coronary artery disease (CAD). Unconjugated bilirubin is conjugated with glucuronic acid through the reaction of uridine 5′-diphosphate-glucuronosyl transferase 1A1 (UGT1A1). The interactions of CAD and the variations in the coding regions of the UGT1A1 gene have never been evaluated. The purpose of this study was to analyze the influence of the UGT1A1 variant on the incidence of CAD. There were 135 participants in this study: 61 in the experimental group, who had CAD, and 74 in the control group, who did not have CAD. The blood samples from all 135 participants were collected and assayed to clarify the relationship between bilirubin and CAD. The assay of the polymerase chain reaction and the sequence of the UGT1A1 gene were examined to find the gene’s polymorphisms. The bilirubin levels for the participants in the control group were significantly higher than for the patients in the CAD group. Although the concentration of bilirubin in the UGT1A1 variant was higher than the wild type for the patients in the CAD group, there was no significant difference in the polymorphism of UGT1A1 between the patients in the CAD group and the participants in the control group.     

High density lipoprotein,apolipoprotein A-1, and coronary artery disease

High density lipoproteins (HDL), one of the main lipoprotein particles circulating in plasma, is involved in the reverse cholesterol transport. Several lines of evidence suggest that elevated levels of HDL is protective against coronary heart disease. The role of HDL in the removal of body cholesterol and in the regression of atherosclerosis add to the importance of understanding the molecular-cellular processes that determine plasma levels of HDL. Factors modulating plasma levels of HDL may have influence on the predisposition of an individual to premature coronary artery disease. Apolipoprotein (apo) A-I is the main apolipoprotein component of HDL and, to a large extent, sets the plasma levels of HDL. Thus, understanding the regulation of apoA-I gene expression may provide clues to raise plasma levels of HDL. This review discusses the various pathways that alter plasma levels of HDL. Since apoA-I is the main protein component of HDL and determines the plasma levels of HDL, this review also covers the regulation of apoA-I gene expression.     

Promoter methylation and functional variants in arachidonate 5-lipoxygenase and forkhead box protein O1 genes associated with coronary artery disease

Coronary artery disease (CAD) is a multifactorial chronic inflammatory disease, which is the most common form of heart disease. This is one of the main causes of death in the United States. Inflammation is one of the key drivers of atherosclerotic plaque development. Forkhead box protein O1 (FOXO1s) family and 5-lipoxygenase make an important contribution to atherosclerosis. The aim of this study was to investigate the methylation pattern and polymorphism analysis of FOXO1 and arachidonate 5-lipoxygenase (ALOX5) promoter genes. We studied 50 patients with CAD and 50 age- and sex-matched healthy controls by high resolution melt technique. Overall, we found significant differences between patients and controls in terms of the promoter methylation of ALOX5 (P > 0.05). But there was no significant difference in FOXO1 promoter methylation between patient and controls. Single nucleotide polymorphisms genotyping of rs12762303 and rs2297627, in ALOX5 and FOXO1 genes were demonstrated a significant correlation between mutant allele and the risk of CAD, respectively. Furthermore, there were significant associations between CT + CC genotype and ALOX5 expression. Our findings demonstrated functional effects of single nucleotide polymorphisms (SNPs) and DNA methylation in ALOX5 on mentioned genes expression and they resulted in CAD progression.     

血清尿酸水平与冠心病的相关性研究

目的:众多关于血清尿酸水平与冠心病发展预后的相关性研究结果不一。本研究旨在通过对上海市第一人民医院入院患者的临床资料分析,研究血清尿酸水平与冠心病之间关系。方法:选择2008年7月至2009年4月上海地区、汉族就诊于我院的患者(123例),按入选排除标准,将入院患者分为冠心病组和对照组,分析尿酸水平与冠心病的关系。结果:男性(81.4%vs 51.6%)、吸烟(49.2%vs 21.9%)、血清尿酸水平升高(6.10±1.2 mg/dl vs 5.37±1.5 mg/dl)为冠心病的危险因素,统计值分别为0.02,0.02,0.005。血尿酸水平升高与血管病变严重程度成正相关,除单支血管病变外,双支血管病变患者尿酸水平为(6.11±1.07)mg/dl,对照组为(5.37±1.55)mg/dl,P0.05,三支病变患者尿酸水平为(6.84±1.29)mg/dl,P0.05。结论:血清尿酸水平升高与冠心病的发生、及病变严重程度密切相关。对冠心病患者的预防和治疗中,应重视对尿酸水平的监测。尿酸水平能否作为冠心病患者预后、转归的预测因子以及降低尿酸水平的治疗能否给冠心病患者带来收益有待进一步的研究。     

冠心病患者运动致QRS延长的临床意义

为探讨冠心病病人由于急性心肌缺血对ＱＲＳ持续时间变化的影响及其意义。本文收集了５３例病人,均进行运动试验和冠脉造影,其中２０例经冠脉造影排除心病,其他３３例经冠脉造影确定为冠心病。结果运动使冠脉正常者ＱＲＳ持续时间缩短,而使冠心病者ＱＲＳ持续时间延长。     

A lack of association between adiponectin polymorphisms and coronary artery disease in a Chinese population

We investigated the association between two single nucleotide polymorphisms (SNPs) in the adiponectin gene (rs822395 and rs266729) and coronary artery disease (CAD) in a case-control study of 198 unrelated Chinese CAD patients (with ≥ 70% coronary stenosis or previous myocardial infarction) and 237 non-CAD controls. The ligase reaction was used to detect SNPs rs822395 and rs266729, and the allelic association of these SNPs with the occurrence and severity of CAD was assessed. There were no significant differences in the genotypic or allelic frequencies of the two SNPs between control and CAD individuals. In addition, there was no association between the two SNPs and the severity of CAD based on the number of diseased vessels. The frequencies of alleles C and G at rs266729 differed significantly between females in the CAD and control groups, but not between males. Female carriers of allele G at rs266729 had a higher risk of CAD compared with allele C carriers (OR = 1.30, 95% CI: 1.09-2.64, p = 0.02). These results indicate a gender-specific effect of the adiponectin gene rs266729 variant in modulating the risk of CAD in women.     

Clinical significance of circulating microRNAs as diagnostic biomarkers for coronary artery disease

Coronary artery disease (CAD) is one of the biggest threats to human life. Circulating microRNAs (miRNAs) have been reported to be linked to the pathogenesis of CAD, indicating the possible role in CAD diagnosis. The present study aimed to explore the expression profile of plasma miRNAs and estimate their value in diagnosis for CAD. 67 Non‐CAD control subjects and 88 CAD patients were enrolled. We conducted careful evaluation by RT‐PCR analysis, Spearman rank correlation coefficients analysis, Receiver Operating Characteristic (ROC) curves analysis and so on. The plasma levels of six miRNAs known to be related to CAD were measured and three of them showed obvious expression change. Circulating miR‐29a‐3p, miR‐574‐3p and miR‐574‐5p were all significantly increased. ROC analysis revealed the probability of the three miRNAs as biomarkers with AUCs (areas under the ROC curve) of 0.830, 0.792 and 0.789, respectively. They were significantly correlated with each other in CAD patients, suggesting the possibility of joint diagnosis. The combined AUC was 0.915, much higher than each single miRNA. Therefore, our study revealed three promising biomarkers for early diagnosis of CAD. The combination of these miRNAs may act more effectively than individual ones for CAD diagnosis.     

A preliminary study of human paraoxonase and PON 1 L/M55–PON 1 Q/R 192 polymorphisms in Turkish patients with coronary artery disease

Paraoxonase 1 (PON 1) is a high‐density lipoprotein (HDL)‐associated enzyme with antioxidant function protecting low‐density lipoprotein (LDL) from oxidation. PON 1 has two amino acid polymorphisms in coding region; L/M 55 and Q/R 192. These polymorphisms modulate paraoxonase activity of the enzyme. PON 1 activity decreases in coronary artery disease (CAD). In the present study, distribution of PON 1 L/M 55 and Q/R 192 polymorphisms and the effect of these polymorphisms on the activities of PON 1, and on the severity of CAD in 277 CAD (+) patient and 92 CAD (?) subjects were examined. PON 1 L/M 55 and Q/R 192 genotypes were determined by PCR, RFLP and agarose gel electrophoresis techniques. Genotype distributions and allele frequencies for PON 1 Q/R 192 polymorphism were not significantly different between controls and CAD (+) patient group (p > 0.05), but in genotype and allele distribution of PON 1 L/M55 polymorphism, there was significantly difference among groups (p < 0.05). Genotype distributions for both polymorphisms were not significantly different between subgroups of single‐vessel disease (SVD), double‐vessel disease (DVD) and triple‐vessel disease (TVD). Serum PON 1 activity was lower in CAD (+) group than in controls and this was also statistically significant (p < 0.001). In both groups, the highest PON activities were detected in LL and RR genotypes. In summary, our results suggest that there is an association between the PON 1 L/M 55 polymorphism of paraoxonase and CAD in Turkish patients but not with PON 1 Q/R 192 polymorphism. However, it is hard to correlate these polymorphisms and severity of CAD. Copyright © 2009 John Wiley & Sons, Ltd.     

NO Level and Endothelial NO Synthase Gene Polymorphism （Glu298Asp） in the Patients with Coronary Artery Disease from the Turkish Population

A healthy endothelium plays a core role in cardiovascu-lar control [1]. In the endothelial cell, nitric oxide (NO) issynthesized by the endothelial nitric oxide synthase (eNOS)encoded by a 26-exon gene (NOS 3) located on chromo-some 7 [2]. Besides its regulatory functions on vasomotortone and blood flow, endothelial NO is known to inhibitthe platelet activation and modulate migration and growthof the vascular smooth muscle [3]. Indirect evidence sug-gests that alterations of the NO pathwa…     

Genome wide DNA methylation profiling for epigenetic alteration in coronary artery disease patients

Background

The alteration in the epigenome forms an interface between the genotype and the environment. Epigenetic alteration is expected to make a significant contribution to the development of cardiovascular disease where environmental interactions play a key role in disease progression. We had previously shown that global DNA hypermethylation per se is associated with coronary artery disease (CAD) and is further accentuated by high levels of homocysteine, a thiol amino acid which is an independent risk factor for cardiovascular disease and is also a key modulator of macromolecular methylation.

Results

We have identified 72 differentially methylated regions (DMRs) that were hypermethylated in CAD patients in the background of varying homocysteine levels. Following deep bisulfite sequencing of a few of the selected DMRs, we found significantly higher methylation in CAD cases. We get six CpG sites in three DMRs that included the intronic region of C1QL4 gene and upstream region of CCDC47 and TGFBR3 genes.

Conclusion

To the best of our knowledge, this is the first study to identify hypermethylated regions across the genome in patients with coronary artery disease. Further validation in different populations is necessary for this information to be used for disease risk assessment and management.     

Carbonyl groups: Bridging the gap between sleep disordered breathing and coronary artery disease

Abstract

Sleep disordered breathing (SDB) is related to coronary artery disease (CAD), but the mechanisms are uncertain. SDB is characterized by periods of intermittent hypoxia and free radical formation. This study tested the hypothesis that carbonylation can be the link between SDB and CAD. It included 14 cases with CAD and 33 controls with <50% coronary narrowing. CAD cases have higher erythrocyte carbonyl levels than controls (p = 0.012). Positive correlation was observed between apnea-hypopnea index (AHI) and erythrocyte carbonyl concentration (ρ = 0.310; p = 0.027). To predict CAD, including as regressors: AHI, erythrocyte carbonyl, gender, age and body mass index, the significant variables in the Poisson multiple regression model were AHI and erythrocytes carbonyl. An increase of 1 pmol/gHb in erythrocyte carbonyl levels increases by 1.8% the risk of CAD and one unit of AHI increases by 3.8% the risk of CAD. The present findings represent the first evidence in humans that SDB may cause CAD through protein carbonylation.     

肠道菌群及其代谢产物氧化三甲胺——冠心病治疗的新靶点

冠心病 (Coronary artery disease,CAD) 是全球发病率和死亡率最高的一种心血管疾病,冠心病和肠道菌群失调密切相关,肠道菌群可能是未来冠心病的重要诊断标志物,改善肠道菌群微环境有望成为治疗冠心病的新途径。作为肠道菌群参与合成的活性代谢产物,氧化三甲胺 (Trimethylamine-N-oxide,TMAO) 水平的升高与心血管疾病患病风险、全因死亡率的增加有关;基础研究表明TMAO可能具有促动脉粥样硬化特性;这些研究提示TMAO可作为预防和治疗冠心病的潜在靶点。文中分析了当前调控肠道菌群及其代谢产物TMAO治疗冠心病的临床及基础性研究,以期为冠心病的治疗提供帮助。     

Identification of differentially expressed genes and the role of PDK4 in CD14+ monocytes of coronary artery disease

Background. Coronary artery disease (CAD) is a chronic inflammatory disease caused by development of atherosclerosis (AS), which is the leading cause of mortality and disability. Our study aimed to identify the differentially expressed genes (DEGs) in CD14⁺ monocytes from CAD patients compared with those from non-CAD controls, which might pave the way to diagnosis and treatment for CAD. Methods. The RNA-sequencing (RNA-seq) was performed by BGISEQ-500, followed by analyzing with R package to screening DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed by R package. In addition, we validated the results of RNA-seq using real-time quantitative polymerase chain reaction (RT-qPCR). Furthermore, we explored the function of selected ten genes in LDL-treated CD14⁺ monocytes by RT-qPCR. Results. a total of 2897 DEGs were identified, including 753 up- and 2144 down-regulated genes in CD14⁺ monocytes from CAD patients. These DEGs were mainly enriched in plasma membrane and cell periphery of cell component, immune system process of biological process, NF-κB signaling pathway, cell adhesion molecules signaling pathway and cytokine–cytokine receptor interaction signaling pathway. In LDL-treated CD14⁺ monocytes, the mRNA expression of pyruvate dehydrogenase kinase 4 (PDK4) was significantly up-regulated. Conclusion. In the present study, we suggested that PDK4 might play a role in progression of CAD. The study will provide some pieces of evidence to investigate the role and mechanism of key genes in the pathogenesis of CAD.     

Effects of cholesterol ester transfer protein Taq1B gene polymorphism on serum lipoprotein levels in Turkish coronary artery disease patients

To evaluate the effect of cholesterol ester transfer protein (CETP) Taq1B gene polymorphism on serum lipid profile in Turkish coronary artery disease (CAD) patients, we investigated Taq1B gene polymorphism of CETP and serum lipid levels in 111 controls and in 173 CAD patients with myocardial infarction. There were no significant differences in the allele distribution at this polymorphic locus between the population sample and patients with coronary artery disease with myocardial infarction. To detect the association between the Taq1B RFLP and serum lipid levels, we determined the serum concentrations of total cholesterol, triglycerides and high density lipoprotein cholesterol (HDL-C) in the subjects studied and correlated the results to the Taq1B RFLP. Patients with Taq B1B1 genotypes had lower HDL-C levels than patients with B2B2 genotype (p = 0.003). Also in control subjects with Taq B1B1 genotype, lower HDL-C levels (p = 0.05) and higher triglyceride levels (p = 0.017) and body mass index (p = 0.05) were observed compared with control subjects with the B1B2 genotype. It was observed that in our population the distribution of CETP Taq1B genotypes is similar to other populations (except Greeks). The present study demonstrates that CETP Taq1B gene polymorphism may be responsible for low HDL cholesterol levels in patients with CAD and in healthy controls in Turkey.