ApoC-III gene polymorphisms and risk of coronary artery disease

Several polymorphisms in the apolipoprotein C-III (apoC-III) gene have been associated with hypertriglyceridemia, but the link with coronary artery disease risk is still controversial. In particular, apoC-III promoter sequence variants in the insulin responsive element (IRE), constitutively resistant to downregulation by insulin, have never been investigated in this connection. We studied a total of 800 patients, 549 of whom had angiographically documented coronary atherosclerosis, whereas 251 had normal coronary arteriograms. We measured plasma lipids, insulin, apoA-I, apoB, and apoC-III and assessed three polymorphisms in the apoC-III gene, namely, T-455C in the IRE promoter region, C1100T in exon 3, and Sst1 polymorphic site (S1/S2) in the 3' untranslated region. Each variant influenced triglyceride levels, but only the T-455C (in homozygosity) and S2 alleles influenced apoC-III levels. In coronary artery disease (CAD) patients, 18.6% were homozygous for the -455C variant compared with only 9.2% in CAD-free group (P < 0.001). In logistic regression models, homozygosity for -455C variant was associated with a significantly increased risk of CAD (OR = 2.5 and 2.18 for unadjusted and adjusted models, respectively) suggesting that it represents an independent genetic susceptibility factor for CAD.     

Genetic polymorphisms, lipoproteins and coronary artery disease risk

Association studies between gene variants (polymorphisms) and measured intermediate phenotypes, such as lipid/lipoprotein levels, or disease endpoints such as coronary artery disease, are commonplace in the literature. But have we learnt anything from the shortcomings in study design and analytical strategies that have resulted in much controversy in this field over the last few years? This review highlights some of these problems. Using the lipoprotein lipase gene as an example, we evaluate new approaches to identifying polymorphisms that will stand up to linkage disequilibrium/association studies with complex disorders in this post Human Genome Project age, and emphasize the importance of gene-environment interaction in assessing the impact of gene variants.     

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.     

Periostin gene polymorphisms, protein levels and risk of incident coronary artery disease

Vascular endothelial growth factor and its receptor the kinase domain receptor play critical roles in the pathogenesis of coronary artery disease. Periostin is an up-regulator of kinase domain receptor expression. The purpose of this study was to determine whether polymorphisms in periostin are associated with the risk of coronary artery disease. Two single nucleotide polymorphisms (SNP C-33G, SNP A-953T) within the promoter region were chosen for further analyses. A case–control study was carried out with patients of Han Chinese ethnicity, which consisted of 492 coronary artery disease cases and 498 controls. Genotyping was performed by means of PCR and restriction fragment length polymorphism (PCR–RFLP) and the plasma level of periostin was measured by enzyme-linked immunosorbent assay (ELISA). In our study, the TT genotype of SNP-A953T was present in the general Chinese population (3.5%), but not in the Han Chinese from Beijing Project (HAPMAP CHB). Plasma periostin concentrations were elevated significantly in patients with coronary artery disease (7.96 ± 8.33 nmol/l) compared with those in healthy volunteers (3.93 ± 1.71 nmol/l) (P = 0.005). There was a significant correlation between the 953T genotype and the plasma level of periostin (r ² = −0.490, P = 0.039). The prevalence of the TT genotype in patients was associated with a slightly lower risk of coronary artery disease (OR = 0.443, 95% CI = 0.200–0.982), but was not significant after correction (OR = 0.427, 95% CI = 0.146–1.250). The periostin-33G allele frequency was not significantly different in cases versus controls. Our data suggest that plasma periostin level may serve as a biomarker for the risk of coronary artery disease, but the periostin polymorphisms SNPC-33G and SNPA-953T were not significantly associated with the risk of coronary artery disease in this Chinese population. Although a major effect of the SNPs in the periostin genes on coronary artery disease susceptibility was excluded, the effect of the A-953T SNP on susceptibility and protein expression needs further investigation.     

Correlation Between Cerebral Infarction and ALOX5AP Gene Expression

Linkage/linkage-disequilibrium analysis studies, based on positional information and gene function, indicated that ALOX5AP gene was an independent risk factor of cerebral infarction in humans; however, this needs to be verified among different populations. Herein, we verified whether ALOX5AP was a risk factor of cerebral infarction in the Chinese Han population. For this purpose, 547 cerebral infarction patients were enrolled as the case group; the control group comprised 794 healthy, age-matched individuals unrelated to case group and had no history of cerebral infarction/transient ischemic attack. Regarding single-nucleotide polymorphism (SNP) selection and ALOX5AP genotyping, we selected four SNP loci (SG13S25, SG13S114, SG13S89, and SG13S32) and determined allelic frequencies. Genotyping of SG13S114 and SG13S32 adopted a method of combining real-time quantitative PCR and allele-specific PCR. A linkage-disequilibrium analysis of ALOX5AP was also performed. We found that the allelic frequencies of SG13S25 and SG13S89 were below 5 % and those of SG13S114 and SG13S32 were above 5 %. We did not find any differences between the case and control groups regarding allele, allele types, and haplotype gene frequencies of two SNP loci. The results indicate that the two genetic polymorphisms of ALOX5AP, SG13S114 and SG13S32, are not associated with cerebral infarction in Chinese Han population.     

Polymorphic variants of ALOX5AP gene and the risk of acute stroke development in the Russian population

A protein capable of activating 5-lipoxygenase (ALOX5AP) is considered a presumable risk factor of acute stroke development. Polymorphic variants of the ALOX5AP gene were examined. Two ALOX5AP gene polymorphisms (SG13S114 (rs10507391) and SG13S32 (rs9551963)), which previously had shown association with the risk of ischemic stroke in other populations, were studied. These single nucleotide polymorphisms were analyzed using a sample of acute stroke patients (N = 1320) and a control sample (N = 467). No statistically significant associations were found between acute stroke and the ALOX5AP gene polymorphisms examined.     

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     

Functional polymorphisms of matrix metallopeptidase-9 and risk of coronary artery disease in a Chinese population

Matrix metallopeptidase-9 (MMP-9) plays a pivotal role in vascular remodeling and development of atherosclerotic lesion. The potentially functional MMP-9 polymorphisms may contribute to the susceptibility of coronary artery disease (CAD). A case–control study composed of 762 CAD cases and 555 CAD-free controls was conducted in a Chinese population to investigate the association between the MMP-9 ?1562 C>T, R279Q, P574R and R668Q polymorphisms and CAD risk. It was found that the variant genotypes of R279Q, P574R and R668Q were associated with a non-significant decreased risk of CAD when compared with their wild-type genotypes, respectively, Furthermore, compared with those without any variant genotypes for these four nonsynonymouse loci, individuals carrying all four variant genotypes (?1562 CT/TT, 279 RQ/QQ, 574 PR/RR and 668 RQ/QQ) had a 51% decreased risk of CAD (adjusted OR = 0.49; 95% CI = 0.26–0.95, P = 0.033). Although no significant main effects were observed for MMP-9 ?1562 C>T locus on CAD risk, variant genotypes of ?1562 C>T were associated with a 2.53 increased risk of CAD in subjects with diabetes mellitus (DM) (95% CI = 1.18–5.45, P = 0.018). In CAD cases, variant genotypes of ?1562 C>T were associated with a significantly increased risk of MI (adjusted OR, 1.48, 95% CI, 1.01–2.20, P = 0.048). These findings suggest that MMP-9 R279Q, P574R and R668Q may have combined effect in the occurrence of CAD and ?1562 CT/TT genotypes may contribute to CAD in diabetics and MI in CAD patients.     

Association of ALOX5AP with ischemic stroke: a population-based case-control study

Arachidonate 5-lipoxygenase activating protein (ALOX5AP) has been reported to demonstrate linkage and association with ischemic stroke and myocardial infarction. However, replication studies have been conflicting and to date, a significant proportion of blacks have not been studied. We prospectively recruited cases of ischemic stroke from all 16 hospitals in the Greater Cincinnati/Northern Kentucky region and demographically matched them to stroke-free population-based controls. Single nucleotide polymorphisms (SNPs) were selected based on association with ischemic stroke in prior studies. Allelic, genotypic and haplotypic association testing was performed using HAPLOVIEW. Multiple logistic regression was used to control for the presence of traditional risk factors including hypertension, diabetes, hypercholesterolemia and smoking. A total of 357 cases and 482 controls were genotyped. The SNPs, rs9579646 and rs4769874 were found to be significantly associated at both allelic (P = 0.019 and P < 10⁻⁴, respectively) and genotypic level with ischemic stroke among whites after correction for multiple testing. Haplotype association was identified with ischemic stroke as well as ischemic stroke subtypes among whites. Although an overall haplotype association with ischemic stroke was identified among blacks no evidence of association among individual haplotypes, alleles or genotypes were observed. Allele frequencies for the SNPs examined were markedly different among whites and blacks. In conclusion, we report significant association of variants of ALOX5AP with ischemic stroke and ischemic stroke subtypes among whites. No significant association was identified among blacks.     

Synergistic effect between apolipoprotein E and apolipoprotein A1 gene polymorphisms in the risk for coronary artery disease

Alterations in lipid metabolism and genetic predisposition are major risk factors for coronary artery disease (CAD). Variations in genes involved in lipid metabolism may act synergistically to confer risk or protection against CAD. The objective of the present study was to determine such interactions in variants of apolipoprotein E and apolipoprotein A1 genes. One hundred and forty subjects with clinically confirmed CAD and 100 unrelated normal subjects participated in the study. Multiple regression analysis was used to relate lipid and apolipoprotein profiles with genotypes. Odd ratios were calculated for various combinations of ApoE and ApoA1 genotypes. Prevalence of ApoE 'E4' and ApoA1 'A' and 'T' alleles was significantly higher in patients than controls. Serum apolipoprotein E and apolipoprotein A1 levels were significantly lower in CAD patients than controls. When lipid parameters were related to genotypes, the polymorphisms associated to various markers were in agreement with previous reports. ApoE 2/4 genotype in combination with either ApoA1 heterozygous GA or CT genotype conferred higher risk of CAD. E3 allele in homozygous or heterozygous state in combination with ApoA1+83 CC genotype conferred highest protection (P < 0.05). Thus, it appears that ApoE and ApoA1 gene variants may act synergistically to associate with risk and protection against CAD.     

Fibroblast growth factor receptor 4 polymorphisms and susceptibility to coronary artery disease

Fibroblast growth factors (FGFs) and their receptors (FGFRs) play crucial roles in vascular smooth muscle cell proliferation and atherosclerosis and, therefore, may potentially affect the development of coronary artery disease (CAD). FGFR4 rs351855 (Gly388Arg) polymorphism has shown to be a risk factor for many diseases. The aim of this study was to investigate the association between FGFR4 polymorphisms and the susceptibility to CAD in the Chinese population. Two polymorphisms, rs351855 (Gly388Arg) and rs641101, were detected by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing in 687 CAD cases and 732 age-matched controls. Data were analyzed using the chi-square test. Results showed that frequencies of GA genotype, AA genotype, and A allele in rs351855 (Gly388Arg) polymorphism were significantly lower in CAD patients than in controls (odds ratio (OR)=0.78, 95% confidence intervals (CIs): 0.62-0.98, p=0.034; OR=0.58, 95% CI: 0.42-0.80, p=0.001; and OR=0.77, 95% CI: 0.66-0.90, p=0.001, respectively). The rs641101 polymorphism did not show any correlation with CAD. Haplotype analysis revealed that rs351855 and rs641101 AG haplotype also had lower frequency in CAD patients (OR=0.79, 95% CI: 0.67-0.92, p=0.002). Our data suggested that the FGFR4 rs351855 (Gly388Arg) polymorphism and AG haplotype (rs351855 and rs641101) could act as protective factors against CAD in the Chinese population and indicated that a single gene polymorphism could have diverse functions in different diseases.     

ADRB2 polymorphisms predict the risk of myocardial infarction and coronary artery disease

Recently, the rs1042713 G > A and rs1042714 C > G polymorphisms in the beta-2adrenergic receptor (ADRB2) gene were shown to be related to atherosclerosisdiseases. Therefore, we performed a systemic meta-analysis to determine whether thetwo functional polymorphisms are related to the risk of myocardial infarction (MI)and coronary artery disease (CAD). We identified published studies that are relevantto our topic of interest. Seven case-control studies, with a total of 6,843 subjects,were incorporated into the current meta-analysis. Our analysis showed a higherfrequency of rs1042713 G > A variant in patients with MI or CAD compared tohealthy controls. A similar result was also obtained with the rs1042714 C > Gvariant under both the allele and dominant models. Ethnicity-stratified subgroupanalysis suggested that the rs1042714 C > G variant correlated with an increasedrisk of the two diseases in both Asians and Caucasians, while rs1042713 G > A onlycontributes to the risk of two diseases in Asians. In the disease type-stratifiedsubgroups, the frequencies of both the rs1042713 G > A and rs1042714 C > Gvariants were higher in the cases than in the controls in both the MI and CADsubgroups. Collectively, our data contribute towards understanding the correlationbetween the rs1042713 G > A and rs1042714 C > G polymorphisms inADRB2 and the susceptibility to MI and CAD.     

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.     

Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: A meta-analysis

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the major enzymes responsible for alcohol metabolism in humans. Emerging evidences have shown that functional polymorphisms in ADH and ALDH genes might play a critical role in increasing coronary artery disease (CAD) and myocardial infarction (MI) risks; however, individually published studies showed inconclusive results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of ADH and ALDH genes with susceptibility to CAD and MI. A literature search was conducted on PubMed, Embase, Web of Science and Chinese BioMedical databases from inception through December 1st, 2012. Crude relative risks (RRs) with 95% confidence intervals (CIs) were calculated. Twelve case–control studies were included with a total of 9616 subjects, including 2053 CAD patients, 1436 MI patients, and 6127 healthy controls. Meta-analysis showed that mutant genotypes (GA + AA) of the rs671 polymorphism in the ALDH2 gene were associated with increased risk of both CAD and MI (CAD: RR = 1.20, 95%CI: 1.03–1.40, P = 0.021; MI: RR = 1.32, 95%CI: 1.11–1.57, P = 0.002). However, there were no significant associations of ADH genetic polymorphisms to CAD and MI risks (CAD: RR = 0.92, 95%CI: 0.73–1.15, P = 0.445; MI: RR = 0.93, 95%CI: 0.84–1.03, P = 0.148). In conclusion, this meta-analysis provides strong evidence that ALDH2 rs671 polymorphism may be associated with increased risks of CAD and MI. However, further studies are still needed to accurately determine whether ADH genetic polymorphisms are associated with susceptibility to CAD and MI.     

Machine learning algorithm-based risk prediction model of coronary artery disease

Molecular Biology Reports - In view of high mortality associated with coronary artery disease (CAD), development of an early predicting tool will be beneficial in reducing the burden of the...     

Impact of MCP-1 and CCR-2 gene polymorphisms on coronary artery disease susceptibility

Coronary artery disease (CAD) was the second leading cause of death during the last 3 years in Taiwan. Smooth muscle cells, monocytes/macrophages, and endothelial cells produce monocyte chemoattractant protein-1 (MCP-1) within atherosclerotic plaques following binding to the chemokine receptor-2 (CCR-2). Previous studies have well-documented the association between MCP-1 expression and susceptibility to, or clinicopathological features, of CAD. This study investigated the relationships between MCP-1-2518A/G and CCR-2-V64I genetic polymorphisms and CAD in the Taiwanese population. A total of 608 subjects, including 392 non-CAD controls and 216 patients with CAD, were recruited and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to evaluate the effects of these two polymorphic variants on CAD. Results indicated a significant association between MCP-1 -2548 gene polymorphism and susceptibility to CAD. GG genotypes (OR = 1.629; 95 % CI = 1.003-2.644), or individuals with at least one G allele (OR = 1.511; 95 % CI = 1.006-2.270), had a higher risk of CAD as compared with AA genotypes. Results also revealed that subjects with at least one A allele of the V64I CCR2 gene polymorphism had significantly increased risk of CAD. G allele in MCP-1-2518 might contribute to higher prevalence of atrial fibrillation in CAD patients (OR = 4.254; p < 0.05). In conclusion, MCP-1-2518G and CCR-2 64I gene polymorphisms represent important factors in determining susceptibility to CAD, and the contribution of MCP-1-2518G could be through effects on atrial fibrillation in CAD patients.