Coronary Artery Disease Susceptibility Research Articles

Abstract 217: Coronary Artery Disease Locus 1p32.2 Harbors a Flow-Sensitive Endothelial Enhancer that Regulates PLPP3

Genome-wide association studies (GWAS) have identified chromosome 1p32.2 as one of the loci most strongly associated with coronary artery disease (CAD) susceptibility; however, the causal mechanism related to this CAD locus remains poorly understood. A unique feature of atherosclerotic vascular disease such as CAD is that atherosclerosis develops preferentially at arterial sites of curvature, branching, and bifurcation where endothelial cells are activated by disturbed blood flow. Recent investigations by us and others strongly implicate PhosphoLipid PhosPhatase 3 (PLPP3, also known as PhosPhatidic-Acid-Phosphatase-type-2B/ PPAP2B or Lipid Phosphate Phosphohydrolase/LPP3) as the causal gene at this locus. PLPP3 encodes an enzyme that suppresses endothelial inflammation and promotes monolayer integrity by hydrolyzing the bioactive lipid lysophosphatidic acid (LPA). Our studies demonstrated that PLPP3 is significantly reduced in vascular endothelium exposed to disturbed flow in vitro and in vivo, as the result of increased miR-92a and reduced KLF2, when compared to cells subjected to unidirectional blood flow. In addition, CAD risk allele at rs17114036 located in 1p32.2 locus is associated with reduced PLPP3 expression in an endothelium-specific manner, shown by expression quantitative trait locus (eQTL). Employing Transposase-Accessible Chromatin using Sequencing (ATAC-Seq), ChIP-Seq, CRISPR/Cas9-based genome editing, luciferase reporters, and allelic imbalance assays, we report here that CAD SNP rs17114036 is located in an endothelial enhancer that is dynamically activated by athero-protective unidirectional flow and deletion of this enhancer causatively reduces PLPP3 expression in vascular endothelium. In addition, CAD risk allele at rs17114036 is associated with reduced activity of this enhancer and its response to unidirectional flow. These results described a new molecular mechanism by which human genetic variance and mechano-transduction converge on critical vascular functions related to atherosclerosis. Moreover, we have engineered innovative polymeric nano-carriers that preferentially target inflamed endothelium and deliver therapeutic nucleotides that intervene in miR92a-PLPP3 signaling in animal models of atherosclerosis.

Associations between LPL gene polymorphisms and coronary artery disease: evidence based on an updated and cumulative meta-analysis.

Lipoprotein lipase (LPL) is widely linked to lipid and lipoprotein metabolism, but its effects on coronary artery disease (CAD) are not clearly elucidated. The aim of the present study was to clarify the association between LPL gene polymorphisms and CAD susceptibility. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated to estimate the strength of the relationship between LPL gene polymorphisms and CAD risk. Comprehensive electronic databases, including PubMed, EMBASE, Web of Science, and the Cochrane Library, were systematically searched. A total of 45 records containing 80 eligible studies were analyzed. The results indicated an increased risk between the LPL D9N polymorphism and susceptibility to CAD in the dominant genetic model (AA + GA vs. GG: OR = 1.46, 95% CI = 1.14–1.87), whereas the LPL HindIII polymorphism showed a protective effect against CAD under all tested models (GG + GT vs. TT: OR = 0.85, 95% CI = 0.75–0.97; GG vs. TT + TG: OR = 0.62, 95% CI = 0.47–0.83; G vs. T: OR = 0.81, 95% CI = 0.71–0.92). No significant association was identified for the LPL N291S and PvuII polymorphisms. Stratification analysis by ethnicity suggested a significant correlation between the LPL S447X polymorphism and CAD susceptibility in Caucasians under the dominant and allele genetic models. In summary, our meta-analysis indicated that the LPL D9N polymorphism was associated with an increased risk of CAD, whereas the S447X and HindIII polymorphisms showed protective effects. There was no association observed between the N291S and PvuII polymorphisms and CAD risk.

Dual Effect of IL-6 -174 G/C Polymorphism and Promoter Methylation in the Risk of Coronary Artery Disease Among South Indians.

Inflammation plays an important role in the pathogenesis of atherosclerosis and coronary syndromes; moreover, various lines of evidence suggest that genetic factors do contribute to the risk of coronary artery disease (CAD). The proinflammatory cytokine IL-6 is a central mediator of inflammation associated with CAD. The present study is aimed to investigate the association of single nucleotide polymorphism in the promoter region of the IL-6 gene (-174 G>C) and methylation with the susceptibility of CAD. Genotyping of IL-6 -174 G/C polymorphism was performed by PCR-RFLP. Methylation-specific PCR method was used to study the IL-6 gene promoter methylation. Analysis of 470 subjects (265 CAD patients and 205 controls) showed association of the -174 G/C variant with the CAD risk in dominant model (OR 1.58, 95% CI, 1.024-2.23, P=0.04). Further, the analysis of the distribution of genotypes and alleles of -174 G>C polymorphism according to clinical features of CAD, revealed significant association of genotype and allele (OR 1.86, 95% CI 1.18-2.84 P=0.01, andOR 1.71, 95% CI 1.09-2.23 P=0.02 respectively) with diabetes, and we found no association with hypertension (OR 0.95, 95% CI 0.57-1.59, P=0.8). We also analyzed the methylation status of IL-6 promoter region between cases and controls showed significant hypo methylation in CAD subjects (OR 2.36, 95% CI 1.51-4.259, P=0.006). Additionally, GC, CC genotypes and C allele carriers show hypomethylation in CAD cases compared to controls (54.58 vs. 76.85%, 29.83 vs. 40% respectively). In conclusion, the promoter polymorphism -174 G/C is associated with CAD risk and further carriers of 'C' allele at -174 locus showed significant hypo methylation which could contribute to increased risk of CAD. The present study highlights the association of allele and genotypes with differential DNA methylation of CpG islands in the IL-6 promoter region which may affect IL-6 gene regulation.

A study of the association of rs12040273 with susceptibility and severity of coronary artery disease in a Chinese Han population

BackgroundThe single nucleotide polymorphism (SNP) rs12040273, a variant of UDP-N–acetylgalactosamine, polypeptide GalNAc-transferase 2, has recently been reported to be significantly associated with development of carotid artery intima-media thickness (IMT) in a Chinese population based on a genome-wide association study. Because IMT is a potent marker of coronary artery disease (CAD), the aim of this study was to evaluate the relation of rs12040273 to susceptibility and severity of CAD in a Chinese Han population.MethodsWe performed a hospital-based case-control study. Three hundred and thirty-one individuals (199 CAD patients and 112 non-CAD controls) undergoing coronary angiography were consecutively enrolled in the study. The Gensini score results were used to assess the severity of CAD. The method of polymerase chain reaction-ligase detection reaction (PCR-LDR) was used to distinguish different genotypes at rs12040273.ResultsThe distribution of genotypes at rs12040273 was comparable between CAD patients and non-CAD controls (P > 0.05). The frequencies of the genotypes were also not significantly associated with the risk of CAD and its severity assessed by the Gensini score method, with the OR of 1.38 (95% CI = 0.80–2.40, P = 0.24) and 1.14 (95% CI = 0.69–1.86, P = 0.60) respectively. However, stratified analysis showed that the serum HDL-C levels of subjects with the CC genotype were significantly higher than those with CT/TT genotypes in non-CAD controls (P = 0.002).ConclusionOur results suggest that the rs12040273 variants might not be associated with the susceptibility of CAD or its severity in a Chinese Han population. Moreover, the CC genotype could be associated with elevated serum HDL-C levels.

The association of polymorphic variants, rs2267788, rs1333049 and rs2383207 with coronary artery disease, its severity and presentation in North Indian population

BackgroundThe polymorphic alleles of APOA5 (rs2266788 (C), rs3135506 (G)), LPA (rs10455872 (A), rs3798220 (G)) and 9p21.3 (rs1333049 (C), rs2383207(A)) have been reported in association with susceptibility of coronary artery disease (CAD) from genome wide association studies. We aimed to assess the association of genetic variants with coronary angiogram proven CAD, severity scored with modified Gensini score and association of risk for myocardial infraction (MI) in North Indian population. MethodsWe recruited 512 angiographic proven CAD patients (mean age 58.1±10.2years) and 272 controls (mean age 50.3±11.1years) with normal coronaries from North Indian population. The genotyping technique polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed for rs2266788, rs3135506 and rs10455872. Amplified refractory mutation system-PCR (ARMS-PCR) was used for genotyping of rs1333049, rs2383207 and rs3798220 genetic variants. ResultsThe polymorphic risk allele of variants rs2266788 (C), rs1333049 (C), rs2383207 (A) and heterozygous polymorphic alleles of rs2266788 (TC) were significantly associated with CAD. The homozygous alleles of rs22667788 (CC) and rs1333049 (CC) had also been significantly associated with CAD. The significance of association of rs2266788 (C, CC, TC) and rs1333049 (C, CC) increases with severity of CAD. The presence of mutant allele of rs2266788 (C) was associated with risk of MI and unstable angina (UA). Also, homozygous risk allele of rs2266788 (CC) significantly associated with risk of MI and UA in patients of chronic stable angina (CSA) patients. Whereas, the risk allele of rs1333049 (C) have shown the association with MI and UA compared to controls. The genetic variants of rs3135506 (G), rs10455872 (A) and rs3798220 (G) have low frequency in our population and reflected no association with CAD. ConclusionThe polymorphic variants of Apo-A5; rs2266788 (C), 9p21.3; rs1333049 (C) rs2383207 (A) are associated with CAD, its severity and exerts the risk of MI in North Indian population.

Paraoxonase 1 Gene Polymorphisms (Q192R and L55M) Are Associated with Coronary Artery Disease Susceptibility in Asian Indians

Background: Coronary artery disease (CAD) is a complex metabolic disorder in which lifestyle and genetic factors are known to play key roles in pathogenesis. The paraoxonase 1 (PON1) enzyme has a defensive effect against CAD progression, as it safeguards low-density lipoproteins (LDLs) from oxidative modifications. The most extensively studied genetic variants in the PON1 gene are Q192R and L55M, which have been related with LDL antioxidative activity and risk of CAD. Objective: The present case-control study intended to examine the Q192R and L55M polymorphisms and their association with the risk of CAD patients in north Indians. Methods: A total of 872 subjects (412 CAD patients and 460 controls) were recruited from north India. The PON1 gene was amplified and genotypes were studies using PCR-RFLP. χ² analysis was performed to compare genotype/allele frequencies in patients and controls. Results: The present study indicated abdominal obesity, elevated body mass index, and dyslipidemia with increased levels of total cholesterol and triglycerides as well as reduced high-density lipoprotein cholesterol in CAD subjects compared to healthy controls (p < 0.05). Logistic regression analysis of the data revealed an association of the RR genotype of the Q192R polymorphism with an about 2-fold elevated risk of CAD (OR = 2.23, 95% CI = 1.47–3.37, p = 0.0001). Contrariwise, the L55M polymorphism did not show significant association with CAD (OR = 1.81, 95% CI = 0.66–4.95, p = 0.326). Conclusions: The Q192R polymorphism in the PON1 gene may be a susceptibility gene associated with increased risk of CAD in an Asian Indian population.

Metabolic Pathway Genes Associated with Susceptibility Genes to Coronary Artery Disease.

Coronary artery disease (CAD) is one of the leading threats to global health. Previous research has proven that metabolic pathway disorders, such as high blood lipids and diabetes, are one of the risk factors that mostly cause CAD. However, the crosstalk between metabolic pathways and CAD was mostly studied on physiology processes by analyzing a single gene function. A canonical correlation analysis was used to identify the metabolic pathways, which were integrated as a unit to coexpress with CAD susceptibility genes, and to resolve additional metabolic factors that are related to CAD. Seven pathways, including citrate cycle, ubiquinone, terpenoid quinone biosynthesis, and N-glycan biosynthesis, were identified as an integrated unit coexpressed with CAD genes. These pathways could not be revealed as a coexpressed pathway through traditional methods as each single gene has weak correlation. Furthermore, sets of genes in these pathways were candidate markers for diagnosis and detection from patients' serum.

ALDH2 gene G487A polymorphism and coronary artery disease: a meta-analysis including 5644 participants.

Several studies indicate the mitochondrial Aldehyde Dehydrogenase‐2 (ALDH2) gene G487A polymorphism may be correlated with coronary artery disease (CAD) susceptibility, but a clear consensus has yet to be reached. To elucidate the relationship between the ALDH2 gene G487A polymorphism and CAD within the Chinese population, a meta‐analysis of 5644 subjects from nine individual studies was performed. Pooled odds ratios (ORs) and their corresponding 95% confidence intervals were assessed using random or fixed‐effect models depending the heterogeneity existence or not. Our meta‐analysis found a significant association between ALDH2 gene G487A polymorphism and CAD in the Chinese population under allele (OR: 1.830, 95% CI: 1.560–2.140, P = 1.36 × 10−13), recessive (OR: 1.920, 95% CI: 1.530–2.390, P = 1.20 × 10−8), dominant (OR: 1.593, 95% CI: 1.336–1.900, P = 2.22 × 10−7), homozygous (OR: 2.280, 95% CI: 1.810–2.870, P = 3.17 × 10−12) and heterozygous genetic models (OR: 3.330, 95% CI: 2.070–5.370, P = 7.81 × 10−7). The positive correlation between the ALDH2 gene G487A polymorphism and CAD makes the mutation a strong candidate as a genetic risk marker for CAD. Through further analysis, we also found that A allele carriers of ALDH2 gene G487A polymorphism may be particularly susceptible to CAD.

WITHDRAWN: The platelet membrane glycoprotein VI genetic polymorphism (rs1613662, 13254T&gt;C) is not associated with the risk of coronary artery disease

// Jian-Quan Luo 1, 2, * , Huan Ren 3, * , Mou-Ze Liu 1, 2 , Ping-Fei Fang 1, 2 and Da-Xiong Xiang 1, 2 1 Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P. R. China 2 Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, P. R. China 3 Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China * These authors contributed equally to this work Correspondence to: Jian-Quan Luo, email: luojianquanxy@csu.edu.cn Keywords: glycoprotein VI; platelets; genetic association; polymorphism; coronary artery disease Received: June 01, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: November 28, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Epub: January 02, 2018 ABSTRACT The platelet membrane glycoprotein VI (GP VI), encoded by GP6 gene, is the essential platelet collagen receptor and medicates platelet activation, adhesion and aggregation. Numerous studies revealed that the GP6 genetic polymorphisms may be associated with the susceptibility of coronary artery disease (CAD). However, a clear consensus has not yet been established. To investigate the association between GP6 genetic polymorphisms and CAD, the databases Pubmed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Wanfang were searched for related studies. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to evaluate the strength of the association by using a random or fixed-effect model. Our analysis confirmed that there was no significant association between the GP6 13254T&gt;C (Ser219Pro, rs1613662) genetic polymorphism and the risk of CAD under an allelic genetic model (OR = 1.00, 95% CI = 0.79&ndash;1.27; P = 0.988), a homozygous genetic model (OR = 1.14, 95% CI = 0.73&ndash;1.80; P = 0.563), a heterozygous genetic model (OR = 1.12, 95% CI = 0.95&ndash;1.33; P = 0.183), a recessive genetic model (OR = 1.11, 95% CI = 0.71&ndash;1.74; P = 0.652). Sensitivity and subgroup analysis indicated the robustness of the results. No publication bias existed between studies. In conclusion, no significant associations between GP6 13254T&gt;C genetic polymorphism and CAD risk were found in this meta-analysis. More large-scale studies on the association of other GP6 genetic polymorphisms and the risk of CAD are needed to be performed in the future.

Genetic variation of CXCR4 and risk of coronary artery disease: epidemiological study and functional validation of CRISPR/Cas9 system

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, while coronary artery disease (CAD) account for a large part of CVDs. Vascular CXCR4 could limit atherosclerosis by maintaining arterial integrity. Here, we conducted a population-based, case-control study to evaluate the associations of common genetic variation within the CXCR4 gene (rs2228014, rs117600832, rs2471859, and rs2322864) with CAD risk in a Chinese population. We found that CXCR4 rs2228014 was significantly associated with 1.29-fold increased risk of CAD (A vs G: OR = 1.29; 95% CI = 1.07–1.55; P = 0.007). The subjects with genotype AA (OR = 1.98; 95% CI = 1.03–3.81; P = 0.041) and AG (OR = 1.27; 95% CI = 1.02–1.58; P = 0.030) have higher risk of CAD, compared with those with genotype GG. Furthermore, both in the CAD patients with diabetes and those without diabetes, rs2228014 was significantly associated with increased risk of CAD (P < 0.05). Additionally, we also validated the significant association for rs2322864 (C vs T: OR = 1.20; 95% CI = 1.00–1.44; P = 0.046). Knockout of CXCR4 gene could significantly impair the capacity of cholesterol efflux (P < 0.01). These findings strongly suggest that CXCR4 polymorphisms might contribute to CAD susceptibility, and the exact biological mechanism awaits further research.

The Associations between Apolipoprotein E Gene Epsilon2/Epsilon3/Epsilon4 Polymorphisms and the Risk of Coronary Artery Disease in Patients with Type 2 Diabetes Mellitus.

Background and Objective: Apolipoprotein E (APOE) plays important roles in lipoprotein metabolism and cardiovascular disease. Evidence suggests the APOE gene epsilon2/epsilon3/epsilon4 (ε2/ε3/ε4) polymorphisms might be associated with the susceptibility of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). However, no clear consensus has yet been established. Therefore, the aim of this meta-analysis is to provide a precise conclusion on the potential association between APOE ε2/ε3/ε4 polymorphisms and the risk of CAD in patients with T2DM based on case-control studies.Methods: Pubmed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases were searched for all relevant studies prior to August 2017 in English and Chinese language. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to assess the strength of the relationships. The between-study heterogeneity was evaluated by Cochran's Q-test and the I2 index to adopt fixed- or random- effect models.Results: A total of 13 studies were eligible for inclusion. There was evidence for significant associations between APOE ε4 mutation and the risk of CAD in patients with T2DM (for ε3/ε4 vs. ε3/ε3: OR = 1.69, 95% CI = 1.38–2.08, P < 0.001; for ε4/ε4 vs. ε3/ε3: OR = 2.72, 95% CI = 1.61–4.60, P < 0.001; for ε4/ε4+ε3/ε4 vs. ε3/ε3: OR = 1.83, 95% CI = 1.52–2.22, P < 0.001; for ε4 allele vs. ε3 allele: OR = 1.64, 95% CI = 1.40–1.94, P < 0.001). In contrast, no significant associations were found in genetic model of APOE ε2 mutation (for ε2/ε2 vs. ε3/ε3: OR = 1.67, 95% CI = 0.90–3.09, P = 0.104; for ε2/ε3 vs. ε3/ε3: OR = 1.18, 95% CI = 0.93–1.51, P = 0.175; for ε2/ε2+ε2/ε3 vs. ε3/ε3: OR = 1.26, 95% CI = 0.88–1.82, P = 0.212; for ε2 allele vs. ε3 allele: OR = 1.34, 95% CI = 0.98–1.84, P = 0.07).Conclusions: The APOE gene ε4 mutation is associated with an increased risk of CAD in patients with T2DM, while the ε2 variation has null association with this disease.

Association of FV G1691A Polymorphism but not A4070G With Coronary Artery Disease.

Coronary artery disease (CAD) is one of the chief causes of death in the world. Several hypotheses have been promoted as for the origin of the disease, among which are genetic predispositions and/or environmental factors. The aim of this study was to determine the effect of factor V (FV) gene polymorphisms (Leiden, G1691A [FVL] and HR2 A4070G) and to analyze their association with traditional risk factors in assessing the risk of CAD. Our study population included 200 Tunisian patients with symptomatic CAD and a control group of 300 participants matched for age and sex. All participants were genotyped for the FVL and HR2 polymorphisms. Multivariate logistic regression was applied to analyze independent factors associated with the risk of CAD. Our analysis showed that the FVL A allele frequency (P < 10–3, odds ratio [OR] = 2.81, 95% confidence interval [CI] = 1.6-4.9) and GA genotype (P < 10–3, OR = 4.03, 95% CI = 2.1-7.6) are significantly more prevalent among patients with CAD compared to those controls and may be predisposing to CAD. We further found that the FVL mutation is an independent risk factor whose effect is not modified by other factors (smoking, diabetes, hypertension, dyslipidemia, and a family history of CAD) in increasing the risk of the disease. However, analysis of FV HR2 variation does not show any statistically significant association with CAD. The FVL polymorphism may be an independent risk factor for CAD. However, further investigations on these polymorphisms and their possible synergisms with traditional risk factors for CAD could help to ascertain better predictability for CAD susceptibility.

Q192R polymorphism in the PON1 gene and familial hypercholesterolemia in a Saudi population.

BACKGROUNDFamilial hypercholesterolemia (FH) is an autosomal dominant condition characterized by abnormal levels of low-density lipoprotein (LDL) in the blood. FH is a risk factor for atherosclerosis and cardiovascular disease. The relationship between the paraoxonase 1 (PON1) gene, atherosclerosis and coronary artery disease has not been studied in Saudi patients.OBJECTIVETo investigate the genetic associations of the Q192R polymorphism in the PON1 gene with FH in Saudi patients.DESIGNCase-control study.SETTINGTertiary care center, Riyadh.METHODSTwo hundred Saudi patients were enrolled in this study, including 100 patients with FH and 100 healthy controls, during the period from January 2012 to March 2013. Serum was separated from coagulated blood (3 mL) and used for analysis of lipid profiles. Genomic DNA was isolated from anticoagulant-treated blood (2 mL). Genotyping for the Q192R polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism analysis, followed by 3% agarose gel electrophoresis.MAIN OUTCOME MEASUREThe strength of association between the Q192R polymorphism and FH in the Saudi population.RESULTSWe confirmed that QR versus QQ (odds ratio [OR]: 1.55; 95% confidence interval [CI]: 1.05–3.43; P=.03), QR+RR versus QQ (OR: 1.98; 95% CI: 1.13–3.49; P=.01), and R versus Q (OR: 1.68; 95% CI: 1.09–2.59; P=.01) in the Q192R polymorphism were associated with FH in the Saudi population.CONCLUSIONIn conclusion, the Q192R polymorphism in the PON1 gene is associated with FH in the Saudi population. Our results confirmed that the R allele, QR, and dominant model genotypes were associated with FH.LIMITATIONOnly a single variant (Q192R) was analyzed, and the medical and family histories of the patients were not known.

Association Between Two Common Polymorphisms of Vitamin D Binding Protein and the Risk of Coronary Artery Disease: A Case-control Study.

SummaryBackgroundCoronary Artery Disease (CAD) is one of the most widespread non-communicable diseases. Vitamin Dbinding protein (VDBP) and its genetic poly morphisms have been highlighted as the susceptible components for CAD. The aim of the present study was to examine the association of VDBP single nucleotide poly morphisms (SNPs) - rs7041 and rs4588 - with CAD susceptibility among the Iranian population.MethodsA total of 143 men with CAD and 145 healthy age-sex matched controls underwent genotyping for the - rs7041 and rs4588 polymorphisms using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Serum level of 25(OH)D was assayed using microplate colorimetric enzyme immunoassay.ResultsWe found a significant association between GG genotype (rs7041) and CAD (p=0.02, OR=0.537 95% CI =0.306-0.944). Regarding rs4588 polymorphism, a significant difference was observed in which the CA genotype (p=0.00032, OR=2.578, 95% CI=1.579-4.208) and allele A (P=0.028, OR=1.491, 95% CI=1.043-2.132) were significantly higher in CAD patients compared to controls. In spite of lower serum levels of 25(OH)D in CAD patients, we found no significant association between these SNPs and Vitamin D serum concentrations.ConclusionWe concluded that VDBP polymorphisms affect the susceptibility to CAD in Iranian men. Therefore, further studies are required to clarify the association of VDBP phenotypes and its serum levels with CAD.

Sex-specific association of SH2B3 and SMARCA4 polymorphisms with coronary artery disease susceptibility.

To determine whether sex differences affect the association between genetic polymorphisms and coronary artery disease (CAD) in the Chinese Han population, we conducted a study comparing the frequency of SH2B3 and SMARCA4 variants in 456 CAD patients (291 men, 165 women) and 685 age-matched controls (385 men, 300 women). Ten single nucleotide polymorphisms (SNPs) in SH2B3 and SMARCA4 were genotyped using MassARRAY technology. Allelic and genotypic models and haplotype frequencies were compared between groups. Logistic regression was used to estimate the CAD risk associated with the genotypes. We found that the “A” alleles in both rs11879293 and rs12232780 of SMARCA4 were associated with CAD risk in men (p = 0.036 and p = 0.001, respectively). The genetic model showed that SH2B3 was associated with CAD susceptibility in both women and men, while SMARCA4 was associated with reduced odds of CAD in men. SH2B3 haplotypes were associated with decreased CAD risk in women (p = 0.007) and increased CAD risk in men (p = 0.047). By providing evidence for the sex-related association between SH2B3 and SMARCA4 gene variants and CAD susceptibility in the Chinese Han population, this study may help define useful diagnostic and preventive markers for these patients.

Polymorphism in ERCC1 confers susceptibility of coronary artery disease and severity of coronary artery atherosclerosis in a Chinese Han population

Excision repair cross-complementing 1 (ERCC1) gene encodes ERCC1 protein, which is mainly responsible for the repair of DNA damage in different diseases including coronary artery atherosclerosis by acting as a rate-limiting element in nucleotide excision repair (NER). Using a three-stage case-control study with 3037 coronary artery disease (CAD) patients and 3002 controls, we investigated associations of three single nucleotide polymorphisms (SNPs) with CAD risk and severity of coronary artery atherosclerosis in Chinese Han population. In the discovery set, the variant allele T of rs11615 was significantly associated with higher CAD risk (adjusted OR = 1.27, P = 0.006) and severity of coronary artery atherosclerosis (adjusted OR = 1.54, P = 0.003). These associations were more remarkable in the merged set (adjusted OR = 1.23, P = 8 × 10−6 for CAD risk; adjusted OR = 1.36, P = 4.3 × 10−5 for severity of coronary artery atherosclerosis). And the expression level of ERCC1 was significantly higher in CAD cases than controls. Multiplicative interactions among SNP rs11615, alcohol drinking, history of T2DM, and history of hyperlipidemia could increase 5.06-fold risk of CAD (P = 1.59 × 10−9). No significant association of rs2298881 and rs3212986 with CAD risk was identified. Taken together, SNP rs11615 in ERCC1 gene might confer susceptibility to CAD and severity of coronary atherosclerosis in a Chinese Han population.

An Updated Systematic Review and Meta-analysis of Association Between Adiponectin Gene Polymorphisms and Coronary Artery Disease.

Coronary artery disease (CAD) is a significant contributor to global health burden. Adiponectin gene single nucleotide polymorphisms (SNPs) have been associated with CAD susceptibility, but with inconsistent results across the studies. We present, in this study, an updated meta-analysis to discern the genetic susceptibility of adiponectin SNPs in relation to CAD. PubMed and EMBASE databases were used to identify the relevant published articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Pooled odds ratios and 95% confidence intervals were generated to assess the strength of the associations. Thirty-five articles with a total of 28,947 participants (mean age 55.3 years, 11,632 cases/17,315 controls, 19,443 males/8353 females, and 1151 persons with unspecified gender data) were included. The dominant, recessive, and additive models were applied. We found that the SNPs +45T>G (rs2241766), -4034A>C (rs822395), and -11391G>A (rs17300539) were linked to CAD development. In addition, +276G>T (rs1501299) SNP was associated with a decreased susceptibility to CAD among Caucasians. We did not find an association between the CAD susceptibility and the -11377C>G (rs266729) SNP. These observations offer new potential genetic biomarker candidates in relation to CAD, and warrant further research in independent world populations.

Two Single Nucleotide Polymorphisms (rs2431697 and rs2910164) of miR-146a Are Associated with Risk of Coronary Artery Disease.

The coronary artery disease (CAD) is one of the most severe cardiovascular diseases. MicroRNA-146a (miR-146a) influences the pathology of cardiovascular diseases. Two single nucleotide polymorphisms (SNPs) of miR-146a (rs2431697 and rs2910164) have been reported to alter the function or expression of microRNA. The purpose of this study is to evaluate the association between miR-146a gene polymorphism and the risk of CAD in the Chinese population. A total of 353 CAD patients and 368 controls were recruited, and SNPs were analyzed by the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and Sequenom MassARRAY system. The gene frequencies of rs2431697 and rs2910164 were significantly different between the two groups. The mutant type (T allele) of rs2431697 and wild type (C allele) of rs2910164 were more frequent in CAD patients. T allele carriers in rs2431697 had an increased CAD risk, while G allele of rs2910164 decreased the risk of CAD significantly. In conclusion, we found that the T allele of rs2431697 was a risk factor of CAD in the Chinese population. Meanwhile, we demonstrated that the G allele of rs2910164 decreased the susceptibility of CAD.

Variant in GALNT3 Gene Linked with Reduced Coronary Artery Disease Risk in Chinese Population.

Our previous study found expression of GALNT3 gene was reduced in coronary artery disease (CAD) patients, and it contributed to endothelial injury by regulating apoptosis and matrix metalloproteinase (MMP) expression. GALNT3 gene may be a potential target for future therapeutic intervention of CAD. However, none reports linking the GALNT3 gene to susceptibility of CAD. This study investigated the variant associations of GALNT3 gene and CAD. Thirteen single nucleotide polymorphism (SNP) in and around the GALNT3 gene were tagged and analyzed in CAD patients (n = 1515) and control individuals (n = 5019), and the SNPs with CAD were tested with multiple logistic regression analysis in an additive genetic model (with one degree of freedom) after adjusting for age and sex. Expression of GALNT3 gene was detected by real-time PCR and Western blot. Luciferase reporter assays were used to detect the allele-specific effect of rs4621175 on transcriptional activity. Two GALNT3 markers, rs13427924 and rs4621175, were significantly associated with CAD (odds ratio [OR] = 0.87, p = 1.01 × 10-3 and OR = 0.75, p = 2.51 × 10-4, respectively), and the risk A allele of rs4621175 was associated with lower GALNT3 expression in both mRNA and protein level; also, A allele showed decreased reporter activity. In addition, we found the level of GALNT3 negatively correlated with MMP-2 gene expression. This study identified GALNT3 as a novel gene that rendered patients susceptible to CAD, and the A allele of a disease-associated variant rs4621175 linked reduced CAD risk through decreased GALNT3 expression. These results confirmed the role of GALNT3 gene in CAD and provided new insights into the genetic regulation of the GALNT3 gene with respect to the pathogenesis of CAD.

Variants in the CXCL12 gene was associated with coronary artery disease susceptibility in Chinese Han population.

BackgroundCoronary artery disease (CAD) is one of the most serious diseases all around the world. Previous studies have shown the function of CXCL12 in the process of atherosclerosis. The aim of this research is to examine whether variants of CXCL12 contribute to CAD.Materials and MethodsTo examine whether variants of CXCL12 contribute to CAD, we selected 6 single nucleotide polymorphisms (SNPs) of CXCL12, and genotyped by Sequenom MassARRAY technology in 597 CAD patients and 685 healthy control. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusted for age and gender. We also analysis the differences in continuous variables among the subjects with three genotypes of related genes were assessed using the ANOVA.ResultsWe found significant differences in apoB concentrations with rs1065297 and rs10793538 different genotype. In the allele model, rs1065297, rs266089 and rs10793538 in CXCL12 gene associated with the risk of CAD. Stratified according to gender, rs266089 and rs2839693 in CXCL12 gene were associated with the risk of CAD in men, while rs1065297 and rs10793538 in CXCL12 gene were associated with the risk of CAD in women. Stratified according to age, rs197452 decreased the risk of CAD in less than 50 years old group. While in more than 50 years old group, not find significant results. Haplotype analysis shown that haplotype “TGCC” in the block increased CAD risk (OR=1.26, 95%CI: 1.00-1.58, p=0.046).ConclusionThis study provides an evidence for polymorphism of CXCL12 gene associated with CAD development in Chinese Han population.