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.     

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).     

The role of PRKCH gene variants in coronary artery disease in a Chinese population

The aim of the present study was to assess the influences of PRKCH gene variants (1425G/A and _15) on the risk of coronary artery disease (CAD) in a Chinese population. Our study population consisted of 470 CAD patients and 434 control subjects. The alleles frequencies of the two variants were significantly higher among CAD patients than control subjects (P = 0.001 for 1425G/A and P = 0.001 for _15, respectively). In the CAD group, the A allele carriers of 1425G/A and _15 polymorphisms had higher low-density lipoprotein cholesterol (LDL-C) levels than homozygote G allele carriers (P = 0.001 and P = 0.021, respectively). In a multiple logistic regression model adjusted for age, sex, body mass index (BMI), etc., a markedly increased risk of developing CAD was found in subjects carrying GA or AA genotype (P = 0.005 and P = 0.018, respectively). In conclusion, we observed that there was a remarkable association of minor alleles (1425G/A and _15) in the PRKCH gene with an elevated risk of CAD and increased levels of LDL-C in this Chinese population.     

Association of Klotho gene polymorphism with hypertension and coronary artery disease in an Iranian population

Background

Klotho, possibly an age-regulating protein, is considered an important factor contributing to the lifespan and pathophysiology of hypertension and coronary artery disease (CAD). The present study was carried out aiming to investigate the association of Klotho-rs564481 (C1818T) gene polymorphism with hypertension and CAD.

Methods

A total of 286 CAD-suspicious subjects were entered into this case-control study. The polymorphism was investigated in hypertensive patients with no CAD (H-Tens, n?=?60); hypertensive patients with CAD (CAD?+?H-Tens, n?=?95); CAD patients with no hypertension (CAD, n?=?61); and non-hypertensive non-CAD subjects, which were regarded as the control group (Ctrl, n?=?70). Genotype and allele frequencies were assessed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

Results

A significant difference was found in allele frequency of Klotho C1818T among the four research groups (P?=?0.03). It was also found that wild-type homozygote subjects were negatively associated with hypertension as compared to heterozygote ones (OR?=?0.07 [95% CI: 0.008–0.69] P?=?0.02). Moreover, in the subgroups older than 57?years old, dominant genetic model demonstrated a negative association with CAD combined with hypertension (OR?=?0.31 [95% CI: 0.10–0.95] P?=?0.04).

Conclusions

In conclusion, Klotho C1818T variant may be associated with a decreased risk of hypertension. Moreover, aging enhanced positive effects of the Klotho polymorphism on CAD combined with hypertension, indicating the possibility that the KLOTHO gene might play a part in the age-related occurrence of CAD combined with hypertension.

     

Relationship between a novel polymorphism of the C5L2 gene and coronary artery disease

Background

C5L2 has been demonstrated to be a functional receptor of acylation-stimulating protein (ASP), which is a stimulator of triglyceride synthesis or glucose transport. However, little is known about the variations in the coding region of the C5L2 gene and their association with coronary artery disease (CAD).

Methodology/Principal Findings

We identified a novel single nucleotide polymorphism (SNP), 698C>T (P233L), in exon 2 using a polymerase chain reaction direct-sequencing method. This nucleotide change causes the amino-acid order from proline to leucine at codon 233. We examined the role of this SNP for CAD using two independent case–control studies: one was in the Han population (492 CAD patients and 577 control subjects) and the other was in the Uygur population (319 CAD patients and 554 control subjects). Heterozygote carriers of the 698CT genotype were more frequent among CAD patients than among controls not only in the Han population (7.3% versus 1.7%) but also in the Uygur population (4.7% versus 1.6%). The odds ratio (OR) for carriers of the 698CT genotype for CAD was 4.484 (95% confidence interval (CI): 2.197–9.174) in the Han group and 2.989 (95% CI: 1.292–6.909) in the Uygur population. After adjustment of confounding factors such as sex, age, smoking, alcohol consumption, hypertension, diabetes, as well as serum levels of triglyceride, total cholesterol, high-density lipoprotein, the difference remained significant in the Han group (P<0.001, OR = 6.604, 95% CI: 2.776–15.711) and in the Uygur group (P = 0.047, OR = 2.602, 95% CI: 1.015–6.671).

Conclusion/Significance

The 698CT genotype of C5L2 may be a genetic maker of CAD in the Han and Uygur population in western China.     

Lack of association between Glu298Asp polymorphism and coronary artery disease in North Indians

Nitric Oxide (NO) is an important molecule carrying number of different functions in humans. Published studies suggest that it may inhibit several key steps involved in the pathogenesis of atherosclerosis. Inhibition or reduction of NO due to Glu298Asp polymorphism may accelerate atherosclerosis. The aim of this study was to determine whether Glu298Asp polymorphism is implicated in the pathogenesis of coronary artery disease (CAD) among North Indian population from the state of Uttar Pradesh, India. We selected 253 CAD patients and 174 healthy, normotensive, non-diabetic controls, which were matched for gender and ethnicity. The Glu298Asp (rs1799983) variant was detected by genotyping subjects, using a polymerase chain reaction followed by restriction fragment length polymorphism. There was no significant difference found in the genotypic and allelic frequencies between patients and controls. Our study indicated that Glu298Asp polymorphism does not play any critical role in the pathogenesis of CAD, at least in North Indian population.     

Plasminogen activator inhibitor-1 4G/5G gene polymorphism and coronary artery disease in the Chinese Han population: a meta-analysis

Background

The polymorphism of plasminogen activator inhibitor-1 (PAI-1) 4G/5G gene has been indicated to be correlated with coronary artery disease (CAD) susceptibility, but study results are still debatable.

Objective and Methods

The present meta-analysis was performed to investigate the association between PAI-1 4G/5G gene polymorphism and CAD in the Chinese Han population. A total of 879 CAD patients and 628 controls from eight separate studies were involved. The pooled odds ratio (OR) for the distribution of the 4G allele frequency of PAI-1 4G/5G gene and its corresponding 95% confidence interval (CI) was assessed by the random effect model.

Results

The distribution of the 4 G allele frequency was 0.61 for the CAD group and 0.51 for the control group. The association between PAI-1 4G/5G gene polymorphism and CAD in the Chinese Han population was significant under an allelic genetic model (OR = 1.70, 95% CI = 1.18 to 2.44, P = 0.004). The heterogeneity test was also significant (P<0.0001). Meta-regression was performed to explore the heterogeneity source. Among the confounding factors, the heterogeneity could be explained by the publication year (P = 0.017), study region (P = 0.014), control group sample size (P = 0.011), total sample size (P = 0.011), and ratio of the case to the control group sample size (RR) (P = 0.019). In a stratified analysis by the total sample size, significantly increased risk was only detected in subgroup 2 under an allelic genetic model (OR = 1.93, 95% CI = 1.09 to 3.35, P = 0.02).

Conclusions

In the Chinese Han population, PAI-1 4G/5G gene polymorphism was implied to be associated with increased CAD risk. Carriers of the 4G allele of the PAI-1 4G/5G gene might predispose to CAD.     

Protective effect of an endothelial lipase gene variant on coronary artery disease in a Chinese population

The aim of the present study was to assess the influence of the endothelial lipase (EL) gene 584C/T variant, which results in a change at codon 111 of the EL gene from threonine to isoleucine, on the risk of coronary artery disease (CAD) in a Chinese population. The study population consisted of 265 CAD patients and 265 age- and sex-matched control subjects. The T allele frequency was significantly lower among CAD patients than among control subjects (18.3% vs. 29.8%; P < 0.001). In both the CAD and control groups, the T allele carriers had higher high density lipoprotein cholesterol (HDL-C) levels than homozygote C allele carriers. In a multiple logistic regression model adjusted for age, sex, body mass index, smoking, hypertension, diabetes, hyperlipidemia, and low density lipoprotein cholesterol, a significantly decreased risk of developing CAD was found in subjects carrying a variant CT or TT genotype (odds ratio = 0.496, 95% confidence interval = 0.341-0.723; P < 0.001), and the significance persisted after further adjustment for HDL-C. In conclusion, our observation that the EL 584T allele was associated with protection from CAD in this Chinese population replicates the findings in a Japanese study, which found a similar association of this allele with acute myocardial infarction, independent of HDL-C levels.     

A case-control study between the gene polymorphisms of polyunsaturated fatty acids metabolic rate-limiting enzymes and coronary artery disease in a Chinese Han population

To investigate the association between the polymorphisms of fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2) and elongation of very long chain fatty acids like 2 (ELOVL2) gene and coronary artery disease (CAD) in a Chinese Han population. Three single nucleotide polymorphisms (SNPs) from these genes were genotyped using PCR-based restriction fragment length polymorphism analysis in 199 CAD cases and 192 controls of Han Chinese origin. rs174556 in the FADS1 gene showed allelic (P=0.002) and genotypic (P=0.030) association with the disease, while there was no disease association for the other two SNPs. The frequency of rs174556 minor allele (T) was significantly higher in the case group than the control group. The trans phase gene–gene interaction analysis showed that the combined genotype of rs174556 (T/T) and rs3756963 (T/T) was weakly associated with the disease (P=0.043). rs174556 in the FADS1 gene is very likely to be associated with CAD in the Chinese Han population.     

Association of growth/differentiation factor 1 gene polymorphisms with the risk of congenital heart disease in the Chinese Han population

There is evidence suggesting that genetic variants of Nodal signaling may be associated with risk of congenital heart diseases (CHDs), in which several polymorphisms, such as Nodal rs1904589, have been considered to be implicated in the accumulation of the genetic burden of CHD risk with interacting genes. We hypothesized that genetic variants of GDF1, a protein that heterodimerizes with Nodal, may be related to increased CHD susceptibility. In this study, four tagSNPs of GDF1 were genotyped in 310 non-syndromic CHD patients and 320 healthy controls by using PCR-based DHPLC and RFLP. The results showed no statistically significant differences in genotype and allele frequencies between CHDs and controls with any of the analyzed variants of GDF1. However, a weak statistical association existed between GDF1 rs4808870 and conotruncal defects (CTDs) (uncorrected P = 0.027). Further stratified analysis for subtype revealed the SNP AA genotype and A allele have statistical significance in pulmonary atresia (PA) (corrected P = 1.01 × 10^?3 and 0.015, respectively), especially in pulmonary atresia with intact ventricular septum (PA + IVS) (corrected P = 1.67 × 10^?3 and 0.034, respectively). Furthermore, two haplotypes, TGGT and CAGT, were found to be significantly associated with increased CHD susceptibility (corrected P = 3.20 × 10^?3 and 2.73 × 10^?7, respectively). In summary, our results provide evidence that genetic variations of the Nodal-like factor, GDF1 may be associated with CHD risk, and these variations contribute at least in part to the development of some subtypes of CTD in the Chinese Han population.     

The association between CD14 gene C-260T polymorphism and coronary heart disease risk: a meta-analysis

Monocyte differentiation antigen CD14 is considered an important cell-activating mediator of inflammatory responses that may result in atherosclerosis, coronary heart disease (CHD), thrombus formation, and myocardial infarction (MI). A common C-260T polymorphism in the promoter of the CD14 gene, the trans-membrane receptor of lipopolysaccharides, has been inconsistently associated with CHD. To investigate this inconsistency, we performed a meta-analysis of 28 studies involving a total of 13,335 CHD cases and 7,979 controls for C-260T of the CD14 gene to evaluate the effect of CD14 on genetic susceptibility for CHD. An overall random effects odds ratio of 1.24 (95 % CI: 1.12–1.36, P < 10^?5) was found for T allele. Significant results were also observed using dominant (OR = 1.34, 95 % CI: 1.17–1.54, P < 10^?4) or recessive genetic model (OR = 1.25, 95 % CI: 1.10–1.41, P = 0.0004). There was strong evidence of heterogeneity (P < 10^?5), which largely disappeared after stratification by ethnicity. After stratified by ethnicity, significant results were found in East Asians; whereas no significant associations were found among Caucasians and other ethnic populations in all genetic models. In the stratified analysis according to sample size, CHD endpoints, and HWE status, significantly increased risks for the polymorphism were found in all genetic models. In conclusion, our results indicate that the CD14 C-260T polymorphism is a risk factor of CHD, especially in East Asians. However, additional very large-scale studies are warranted to confirm our results.     

Cox-2 gene polymorphism and IL-6 levels in coronary artery disease

Coronary artery disease is one of the leading causes of mortality and diabetes mellitus is one of its main risk factors due to microvascular and macrovascular complications, such as atherosclerosis. Atherosclerosis is now known to be an inflammatory process mediated by prostaglandins and several interleukins. As both are important in inflammatory processes, we examined Cox-2 (-765G > C) polymorphism and interleukin-6 levels in coronary artery disease patients compared to healthy controls. We also divided the patients into diabetic and non-diabetic groups to check the effects of diabetes mellitus separately. We found that the GG allele frequency was significantly higher in the patient group. Patients with the GG genotype had an approximately 2.78-fold higher risk of coronary artery disease. We also found that the Cox-2 (-765G > C) polymorphism is associated with lower interleukin-6 levels, which decreased in the order: GG > GC > CC.     

Further evidence for the contribution of the vascular endothelial growth factor gene in coronary artery disease susceptibility

Coronary artery disease (CAD) receives intensive attentions in the research of cardiovascular diseases, due to its high incidence and severe impact on the quality of life vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, has been strongly implicated in the pathogenesis of CAD. Genetic markers in different regions of the VEGF gene have a plausible role in modulating the risk of CAD. To identify the markers contributing to the genetic susceptibility to CAD, we examined the potential association between CAD and 10 single nucleotide polymorphisms (SNPs, rs699947, rs1570360, rs2010963, rs833068, rs3024997, rs3025000, rs3025010, rs3025020, rs3025030, rs3025039) of the VEGF gene using the MassARRAY system. Participants included 242 CAD patients and 253 healthy controls from a Chinese Han Population (He'nan Province, China). The allelic or genotypic frequencies of the rs699947 (5′ untranslated regions, 5′UTR) and rs2010963 (5′UTR) polymorphisms in the CAD patients were significantly different from those in the healthy controls. The CAD patients had significantly higher frequency of the rs699947 A allele (χ² = 11.141, P = 0.001, OR = 1.665, 95% CI = 1.232–2.250) and rs2010963 C allele (χ² = 13.593, P = 0.0002, OR = 1.611, 95% CI = 1.249–2.077). Strong linkage disequilibrium was observed in the rs699947–rs1570360–rs2010963 haplotype block (D’ > 0.9). Significantly more C–G–C haplotypes (P = 0.040) and significantly fewer C–G–G haplotypes (P = 0.0004) were found in the CAD patients. The possible association of rs699947 and rs2010963 with CAD risks warrant confirmation in independent case–control studies and may be informative for future investigations on the pathogenesis of CAD.     

The Q192R polymorphism of the paraoxonase 1 gene is a risk factor for coronary artery disease in Saudi subjects

Paraoxonase-1 (PON1) is a HDL-bound antioxidant enzyme that protects LDL from oxidative modification. Discovery of the antioxidant properties of PON1 led to extensive research on its role in the initiation and progression of atherosclerosis. The Q192R (rs662; A/G) polymorphism, which results in the glutamine to arginine substitution at position 192, of the PON1 gene has been linked to increased atherosclerosis risk in several but not all population studies. Besides genetic factors, environmental variables and ethnicity have been implicated as factors responsible for the ambiguity in relating the PON1 gene with atherosclerotic risk. Here, we tested the association of the Q192R polymorphism with coronary artery disease (CAD) in Saudi ethnic subjects taking environmental factors into consideration. The genomic DNA samples from 121 angiographically confirmed CAD cases and 108 normal healthy control subjects were genotyped by PCR–RFLP analysis. The distribution of QQ, QR, and RR genotypes was significantly different between cases and controls (p < 0.005). The RR genotype was associated with CAD risk independently of several established risk factors including age, gender, smoking, obesity, and diabetes (OR 2.2, 1.4–7.4, p < 0.01). Genotype-based stratification of demographic and biochemical data revealed that the RR genotype has proatherogenic properties. This study, thus, identifies the Q192R polymorphism as an additional risk factor for CAD in the Saudi population and suggests that it may have prognostic value. The negative effect of this genetic variant is presumably due to the diminished ability of the RR variant genotype of PON1 to blunt LDL oxidation.     

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.     

Fibroblast growth factor receptor 4 Gly388Arg polymorphism associated with severity of gallstone disease in a Chinese population

The etiology of gallstone disease is multifactorial; supersaturation of bile with cholesterol is a primary cause for gallstone formation. In previous studies, we found that fibroblast growth factor receptor 4 (FGFR4) plays an important role in maintaining bile acid homeostasis by regulating the expression of cholesterol 7α-hydroxylase (CYP7A1), a rate-limiting enzyme for bile acid biosynthesis. The Gly388Arg (G-388R) polymorphism of FGFR4 affects stabilization and activation of FGFR4. Consequently, we studied the FGFR4 gene as a candidate gene for genetic susceptibility to gallstone disease. We found that overexpression of FGFR4, especially the G-388R mutant of FGFR4, inhibits luciferase activity of CYP7A1 reporter in HepG2 cells, indicating that the G-388R mutant of FGFR4 may have greater inhibitory activity against bile acid biosynthesis. To investigate the association of FGFR4 polymorphism with gallstone disease, 117 patients with gallstone disease and 457 controls were genotyped for FGFR4 polymorphism G-388R by PCR-RFLP. Although the incidence of gallstone disease was not greater in patients with the FGFR4 RR genotype, the ratio of gallstone patients with acute cholecystitis in the FGFR4 RR genotype (42%) was significantly higher than that in other genotypes of FGFR4 (P = 0.019). In conclusion, the FGFR4 polymorphism is a genetic risk factor contributing to aggravation of gallstone disease.     

ATP-binding cassette transporter A1 R219K polymorphism and coronary artery disease in Chinese population: a meta-analysis of 5,388 participants

The ATP-binding cassette transporter A1 (ABCA1) R219K gene polymorphism has been suggested to lower the risk of coronary artery disease (CAD). However, research results remain debatable. Meta-analysis involving 2,730 CAD patients and 2,658 controls was performed to investigate the relationship between ABCA1 R219K gene polymorphism and CAD in Chinese population. A total of 14 studies which were obtained from electronic databases were analyzed. The pooled odds ratios (ORs) and their corresponding 95?% confidence intervals (95?% CIs) were estimated by a random effect model. A significant association between ABCA1 R219K gene polymorphism and CAD was found in the Chinese population under the following genetic models: an allelic genetic model (OR 0.70, 95?% CI 0.62–0.78, P?<?0.00001), a recessive genetic model (OR 0.51, 95?% CI 0.41–0.64, P?<?0.00001), an additive genetic model (OR 0.816, 95?% CI 0780–0.855, P?=?0), a dominant genetic model (OR 1.326, 95?% CI 1.232–1.427, P?=?0), a homozygote genetic model (OR 0.640, 95?% CI 0.575–0.712, P?=?0), and a heterozygote genetic model (OR 0.640, 95?% CI 0.575–0.712, P?=?0). The K allele of the ABCA1 R219K gene has a protective role for CAD risk in Chinese population and is possibly associated with decreased CAD susceptibility.