Coronary Artery Disease Susceptibility Research Articles

Pharmacogenetic loci for rosuvastatin are associated with intima-media thickness change and coronary artery disease risk.

Aim: Polymorphisms at LPA, LDLR, APOE, APOC1, MYLIP and ABCG2 are attractive targets for assessment of their impact on lipid-lowering therapy with rosuvastatin. The present study investigated whether polymorphisms at these genes are associated with the risk of coronary artery disease (CAD) development, and reduction of atherogenic lipids and carotid intima-media thickness (CIMT) in CAD patients, taking rosuvastatin. Materials & methods: 190 CAD patients and 1697 subjects were enrolled in pharmacogenetic and genetic association study, respectively. SNP genotyping was done using the MassARRAY-4 system. Results:MYLIP rs6924995, rs3757354, APOC1 rs445925, LDLR rs6511720, APOE rs7412, ABCG2 rs2199936, rs1481012 variants were significantly associated with CAD susceptibility (p=0.016, 0.0003, <0.0001, <0.0001, 0.013, 0.016, 0.0035, respectively), as well as with CIMT regression (except ABCG2 variants; p=0.05, 0.039, 0.039, 0.016, 0.0065), and changes in plasma lipids during rosuvastatin therapy. Conclusion: The studied polymorphisms possess pleiotropic effects on plasma lipids and CIMT, CAD susceptibility, and determine lipid-lowering response to rosuvastatin.

Biological and Clinical Implications of TNF-α Promoter and CYP1B1 Gene Variations in Coronary Artery Disease Susceptibility.

Cardiovascular diseases (CVD) are important causes of death worldwide. Atherosclerosis is a chronic inflammatory disorder. It is the major cause of CVD and is manifested by ischemic heart disease or coronary artery disease (CAD). TNF-α is a pro-inflammatory cytokine that regulates immune response and promotes the development of atherosclerosis. Cytochrome p450 1B1 (CYP1B1) is an enzyme involved in the metabolism of endogenous and exogenous substrates. This study aimed at examining the association of TNF-α rs1800629 G>A and CYP1B1 rs1056827 G>T gene polymorphisms with CAD susceptibility in an Indian cohort. AS-PCR and direct DNA sequencing were used to examine the association of TNF-α rs1800629 G >A and CYP1B1 rs1056827 G>T gene polymorphism with CAD in an Indian cohort. A total of 100 clinically confirmed cases of CAD and 110 matched apparently healthy controls were genotyped. Allelic and genotypic frequencies did not deviate from Hardy-Weinberg equilibrium in the controls (p>0.05) for TNF-α G-308A and CYP1B1 rs1056827G>A. There was no significant difference between the TNF-α rs1800629 A>G genotype distribution between cases and controls (P-value >0.05). A significant difference was observed between the CYP1B1 rs1056827 G>T genotype distribution between CAD cases and controls (p<0.0003). Our result indicated that in the codominant model, the GA genotype of the CYP1B1 rs1056827 G>T was associated with CAD with OR= 2.21(1.17 to 4.15), RR=1.38(1.07 to 1.78), and p<0.013. In the dominant model, the (GA+AA) genotype was associated with CAD with OR=2.79(1.54 to 5.05) and p<0.007. The CYP1B1 rs1056827 'A' allele was associated with CAD with OR = 2.30 (1.55 to 3.42) and p< 0.0001. Our results indicated that TNF-α 1800629 gene polymorphism was strongly associated with hypercholesteremia (p<0.0009), HDL (p<0.0001), TGL (p<0.039), hypertension (p<0.0001), and smoking (p<0.0001) in patients with Coronary Artery Disease. Similar correlations of CYP1B1 rs1056827 genotypes were reported with cholesterol (p<0.020), HDL (p<0.002), LDL (p<0.006), hypertension (p<0.03), and smoking (p<0.005). It was reported that the GA genotype of the CYP1B1 rs1056827 G>T was strongly associated with susceptibility to Coronary Artery Disease with OR= 2.21(1.17 to 4.15)) and p<0.013, and similarly, its A allele was associated with predisposition to CAD with OR = 2.30 (1.55 to 3.42) and p< 0.0001. Our results indicated that TNF-α 1800629 gene polymorphism is not associated with predisposition to Coronary Artery Disease. Nevertheless, these results should be taken with caution and further validated with larger-scale studies before being introduced in the clinical setting.

Effects of IL-32 polymorphisms and IL-32 levels on the susceptibility and severity of coronary artery disease.

BackgroundInterleukin‐32 (IL‐32) has long been proposed as a biomarker for coronary artery disease (CAD). We aimed to evaluate the association between IL‐32 levels and coronary stenosis severity, IL‐32 polymorphisms rs28372698 and rs4786370, and CAD susceptibility.MethodsA total of 362 patients with definite or suspected CAD that underwent angiography were recruited (CAD group, n = 175; nonobstructive CAD group, n = 56; control group, n = 131). The severity of coronary stenosis was assessed using the Gensini score and the number of diseased vessels. IL‐32 levels were determined using enzyme‐linked immunosorbent assay. Gene polymorphisms were genotyped using PCR and sequencing techniques.ResultsIL‐32 levels were significantly different at different levels of coronary artery stenosis (p < 0.05), and logIL‐32 was positively correlated with the Gensini score (r = 0.357, p < 0.01). Multivariate logistic regression analysis revealed that IL‐32 was independently associated with CAD (OR = 6.526, 95% CI: 3.344–12.739, p < 0.01). The receiver operating characteristic analysis revealed the area under the curve for discriminating the CAD and Gensini score were 0.605 and 0.613, respectively. Furthermore, IL‐32 levels were significantly higher before percutaneous coronary intervention (PCI) than at 7 days post‐PCI (p = 0.012). The homozygous TT genotype and T allele of rs28372698 were found to be associated with increased risk of CAD, while TT homozygosity and the T allele of rs4786370 with reduced risk of CAD (p < 0.05). However, both SNPs had no obvious effect on IL‐32 levels or coronary stenosis severity in patients with CAD.ConclusionTo the best of our knowledge, our study is the first to show that rs28372698 and rs4786370 are associated with CAD susceptibility in Chinese Han population. We also suggest that plasma IL‐32 levels may be indicative of coronary artery stenosis and the efficacy of PCI and provide guidance for risk stratification and disease management.

Abstract 12985: Genetic Susceptibility for Coronary Artery Disease Accentuates the Cardiovascular Disease Risk Associated With Air Pollution

Introduction: Air pollution (particulate matter of diameter &lt;2.5 μm, PM 2.5 ) and genetic risk for coronary artery disease (CAD) each associate with cardiovascular disease (CVD). It is unknown whether genetic risk for CAD enhances CVD risk associated with air pollution exposure. Hypothesis: We tested the hypothesis that high genetic risk for CAD accentuates the adverse impact of air pollution on CVD, (as coronary artery calcium [CAC]) and major adverse cardiovascular events [MACE]). Methods: Participants (N=9340, median age 66 yrs, 49% male) in the Mass General Brigham Biobank with genetic and air pollution data were studied. Genome wide polygenic risk score for CAD (PRS CAD ) and principal components of ancestry (PCI) were determined. Average PM 2.5 exposure one year before each person’s enrollment was derived using home addresses and Environmental Protection Agency data. CAC was assessed on those with available CT images (N=548). MACE and CVD risk factors were evaluated via International Classification of Diseases codes. Socioeconomic status (SES) was assessed as residential zip code level income using US Census data. The presence of an interaction between high PM 2.5 and PRS CAD vs. MACE was tested. Results: The Combination of high PRS CAD and PM 2.5 (both ≥ median vs. others) associated with greater CAC [standardized β (95% CI): 0.13 (0.06, 0.19), p=0.0002, Fig.1A ] after adjusting for age, sex, and PCI and with further adjustment for CVD risk factors (p=0.007). Over 5 years median follow up, 1139 subjects experienced first time MACE. Combined high PRS CAD and PM 2.5 also associated with higher MACE risk [OR (95% CI): 1.20 (1.15, 1.25), p&lt;0.001, p (interaction) &lt;0.001, Fig.1B ] after adjusting for age, sex, and PCI and with further adjustment for CVD risk factors (p&lt;0.001) and SES (p&lt;0.001). Conclusions: Among individuals exposed to air pollution, genetic risk for CAD accentuates CAC and MACE risk in a graded manner. Genetic context may impact the health effects of air pollution.

Association between Paraoxonase-1 p.Q192R Polymorphism and Coronary Artery Disease susceptibility in the Colombian Population.

BackgroundParaoxonase-1 (PON1), a glycoprotein associated with serum high-density lipoprotein (HDL), has a central role in metabolizing lipid peroxides, exhibiting antiatherogenic properties. The polymorphism p.Q192R has been previously associated with coronary artery disease (CAD) susceptibility and clopidogrel response.PurposeWe aimed at investigating the association of PON1 p.Q192R with CAD and clopidogrel response in Colombian population.Patients and MethodsThe study was conducted among 163 patients diagnosed with CAD and treated with clopidogrel. The allele frequencies for the PON1 192Q and 192R alleles were determined in cases and Latin-American controls obtained from the public database gnomAD (n = 17,711). Response to clopidogrel was determined by assessing the platelet function using the INNOVANCE PFA-200 System. We determined the association between PON1 p.Q192R polymorphism, increased susceptibility to CAD and high on-treatment platelet reactivity (HPR) by using odds ratio (OR) and 95% confidence interval (CI) on four genetic models.ResultsThe allele frequencies for the PON1 192Q and 192R alleles were 0.60 and 0.40, respectively. The allele distribution was found to be statistically different from the control group and other ethnic groups. The allele 192R was positively associated with decreased susceptibility to CAD under a dominant model (OR, 0.58; 95% CI, 0.42–0.8; P < 0.01). We found no association between the polymorphism and HPR.ConclusionWe propose that PON1 p.Q192R is a potentially useful marker for CAD susceptibility in the Colombian population and lacks association with HPR under clopidogrel treatment.

Increased classical monocyte subsets in South Asians compared to White Caucasians at risk for coronary atherosclerosis

Abstract Background South Asians (SA) have an increased prevalence of coronary artery disease (CAD) and myocardial infarction compared with age- and sex-adjusted White Caucasians (WC). The mechanism for this increased risk is poorly understood. While classical CD14++CD16- monocytes act as independent predictors of cardiovascular disease, differences in the distribution of monocyte subsets between SA and WC have not been established. Purpose We aimed to determine if differences exist in monocyte subsets between SA and WC at risk for CAD. Methods Our cohort consisted of 119 consecutively enrolled patients (59 SA, 60 WC) at intermediate or higher risk for CAD by the INTERHEART score using self-reported history and physical exam. A single blood sample was collected prospectively for the purpose of monocyte analysis. Flow cytometry using dual colour fluorescence (CD14, CD16) within the monocyte gate was used to identify monocyte subsets (classical, intermediate and non-classical) by staff blinded to the individuals' characteristics. Variables were compared using Mann-Whitney U test and Chi-squared test, as appropriate. Eta coefficient was calculated to analyze the relationship between ethnicity and proportion of monocyte subsets. Eta squared values were calculated to assess the impact of ethnicity on monocyte subset proportions. Results The SA group consisted of 64% males with a mean age of 54 (± 9), while the WC group consisted of 55% males with a mean age of 59 (± 7). Both groups had similar body mass index, rates of hypertension, dyslipidemia and family history of premature CAD. Compared to WC, SA had higher prevalence of diabetes (36% vs. 13%, p=0.005) and hemoglobin A1C levels (6.0±1.1% vs. 5.6±0.6%, p&amp;lt;0.001). SA patients had a higher proportion (85.3±10.7% vs. 81.4±11.0%, p=0.009) and total level (449.0±180.4 vs. 388±127.4, p=0.010) of classical CD14++CD16- monocytes compared to WC. There was no difference between the two groups in the proportion of intermediate CD14++CD16+ and non-classical CD14+CD16++ monocytes. There was no association between diabetes and the proportion of monocyte subsets. Ethnicity had a moderate association with the proportion of classical CD14++CD16- monocytes (Eta coefficient = 0.525) with a large effect size (Eta squared = 27.5%). The association of ethnicity with intermediate CD14++CD16+ and non-classical CD14+CD16++ monocytes was either weak or negligible with minimal to no effect size. Conclusion In patients with substantive risk for CAD, SA had a significantly higher proportion and level of classical CD14++CD16- monocytes compared to WC. Our findings provide a novel insight into the potential mechanism of increased CAD susceptibility amongst SA compared to WC. Future studies are needed to determine whether these ethnic differences in the distribution of monocyte subsets can predict susceptibility to developing CAD and suffering atherothrombotic events. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Cardiology Academic Practice Plan grant at the University of British Columbia

MONOCYTE SUBSETS HETEROGENEITY AND CORONARY ATHEROSCLEROSIS IN SOUTH ASIANS COMPARED TO WHITE CAUCASIANS

BACKGROUND South Asians (SAs) have an increased prevalence of coronary artery disease (CAD) and myocardial infarction compared with age- and sex-adjusted White Caucasians (WCs). The mechanism for this increased risk is poorly understood. While classical CD14++CD16- monocytes act as independent predictors of cardiovascular disease, differences in the distribution of monocyte subsets between SA and WC have not been established. We aimed to determine if differences exist in monocyte subsets between SAs and WCs at risk for CAD. METHODS AND RESULTS 119 consecutive patients (59 SA, 60 WC) of at least intermediate CAD risk by the INTERHEART score were prospectively enrolled. Patients with history of malignancy, age > 70, GFR < 30 or on dialysis were excluded. A single blood sample was collected for monocyte analysis. Flow cytometry using dual colour fluorescence (CD14, CD16) within the monocyte gate was used to identify monocyte subsets (classical, intermediate, and non-classical) by staff blinded to the individuals’ characteristics. The SA group consisted of 64% males with a mean age of 54 (+/- 9), while the WC group consisted of 55% males with a mean age of 59 (+/- 7). Both groups had similar body mass index, rates of hypertension, dyslipidemia and family history of premature CAD. Compared to WCs, SAs had higher prevalence of diabetes (36% vs. 13%, p = 0.005) and hemoglobin A1C levels (6.0 +/- 1.1% vs. 5.6 +/- 0.6%, p < 0.001). SA patients had a higher proportion (85.3 +/- 10.7% vs. 81.4 +/- 11.0%, p = 0.009) and total level (449.0 +/- 180.4 vs. 388 +/- 127.4, p = 0.010) of classical CD14++CD16- monocytes compared to WCs. There was no difference between the two groups in the proportion of intermediate CD14++CD16+ and non-classical CD14+CD16++ monocytes (see Figure 1). There was no association between diabetes and the proportion of monocyte subsets. Ethnicity had a moderate association with the proportion of classical CD14++CD16- monocytes (Eta coefficient = 0.525) with a large effect size (Eta squared = 27.5%). The association of ethnicity with intermediate CD14++CD16+ and non-classical CD14+CD16++ monocytes was either weak or negligible with minimal to no effect size (see Table 1). CONCLUSION In patients with substantive risk for CAD, SAs had a significantly higher proportion and level of classical CD14++CD16- monocytes compared to WCs. Our findings provide a novel insight into the potential mechanism of increased CAD susceptibility amongst SAs compared to WCs. South Asians (SAs) have an increased prevalence of coronary artery disease (CAD) and myocardial infarction compared with age- and sex-adjusted White Caucasians (WCs). The mechanism for this increased risk is poorly understood. While classical CD14++CD16- monocytes act as independent predictors of cardiovascular disease, differences in the distribution of monocyte subsets between SA and WC have not been established. We aimed to determine if differences exist in monocyte subsets between SAs and WCs at risk for CAD. 119 consecutive patients (59 SA, 60 WC) of at least intermediate CAD risk by the INTERHEART score were prospectively enrolled. Patients with history of malignancy, age > 70, GFR < 30 or on dialysis were excluded. A single blood sample was collected for monocyte analysis. Flow cytometry using dual colour fluorescence (CD14, CD16) within the monocyte gate was used to identify monocyte subsets (classical, intermediate, and non-classical) by staff blinded to the individuals’ characteristics. The SA group consisted of 64% males with a mean age of 54 (+/- 9), while the WC group consisted of 55% males with a mean age of 59 (+/- 7). Both groups had similar body mass index, rates of hypertension, dyslipidemia and family history of premature CAD. Compared to WCs, SAs had higher prevalence of diabetes (36% vs. 13%, p = 0.005) and hemoglobin A1C levels (6.0 +/- 1.1% vs. 5.6 +/- 0.6%, p < 0.001). SA patients had a higher proportion (85.3 +/- 10.7% vs. 81.4 +/- 11.0%, p = 0.009) and total level (449.0 +/- 180.4 vs. 388 +/- 127.4, p = 0.010) of classical CD14++CD16- monocytes compared to WCs. There was no difference between the two groups in the proportion of intermediate CD14++CD16+ and non-classical CD14+CD16++ monocytes (see Figure 1). There was no association between diabetes and the proportion of monocyte subsets. Ethnicity had a moderate association with the proportion of classical CD14++CD16- monocytes (Eta coefficient = 0.525) with a large effect size (Eta squared = 27.5%). The association of ethnicity with intermediate CD14++CD16+ and non-classical CD14+CD16++ monocytes was either weak or negligible with minimal to no effect size (see Table 1). In patients with substantive risk for CAD, SAs had a significantly higher proportion and level of classical CD14++CD16- monocytes compared to WCs. Our findings provide a novel insight into the potential mechanism of increased CAD susceptibility amongst SAs compared to WCs.

Patient Endothelial Colony-Forming Cells to Model Coronary Artery Disease Susceptibility and Unravel the Role of Dysregulated Mitochondrial Redox Signalling.

Mechanisms involved in the individual susceptibility to atherosclerotic coronary artery disease (CAD) beyond traditional risk factors are poorly understood. Here, we describe the utility of cultured patient-derived endothelial colony-forming cells (ECFCs) in examining novel mechanisms of CAD susceptibility, particularly the role of dysregulated redox signalling. ECFCs were selectively cultured from peripheral blood mononuclear cells from 828 patients from the BioHEART-CT cohort, each with corresponding demographic, clinical and CT coronary angiographic imaging data. Spontaneous growth occurred in 178 (21.5%) patients and was more common in patients with hypertension (OR 1.45 (95% CI 1.03–2.02), p = 0.031), and less likely in patients with obesity (OR 0.62 [95% CI 0.40–0.95], p = 0.027) or obstructive CAD (stenosis > 50%) (OR 0.60 [95% CI 0.38–0.95], p = 0.027). ECFCs from patients with CAD had higher mitochondrial production of superoxide (O2−–MitoSOX assay). The latter was strongly correlated with the severity of CAD as measured by either coronary artery calcium score (R2 = 0.46; p = 0.0051) or Gensini Score (R2 = 0.67; p = 0.0002). Patient-derived ECFCs were successfully cultured in 3D culture pulsatile mini-vessels. Patient-derived ECFCs can provide a novel resource for discovering mechanisms of CAD disease susceptibility, particularly in relation to mitochondrial redox signalling.

CALM1 rs3179089 polymorphism might contribute to coronary artery disease susceptibility in Chinese male: a case-control study.

Calmodulin 1 (CALM1) mutations are involved in the development of coronary artery disease (CAD). However, the relationship of CALM1 rs3179089 polymorphism with CAD is unknown. This study aimed to identify the relationship of CALM1 rs3179089 polymorphism with CAD susceptibility, CALM1 expression, blood pressure, blood glucose, blood coagulation and serum lipid levels of CAD patients. 550 CAD patients and 550 control subjects were genotyped for CALM1 using Sequenom MassARRAY technology. CALM1 expression level was measured by quantitative real time polymerase chain reaction (qRT-PCR). CALM1 mRNA expression was higher in CAD patients than that in control subjects (P < 0.001). CAD patients with CC genotype had higher CALM1 mRNA expression level than control subjects with CC genotype (P = 0.006). Genotypic frequency of rs3179089 was different between male patients of CAD and control subjects (P = 0.045). Rs3179089 polymorphism was related to CAD risk of males in recessive model (P = 0.039). Moreover, rs3179089 polymorphism was associated with systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG), and D-Dimer (D-D) level of patients with CAD in recessive model (P = 0.013 for SBP; P = 0.034 for DBP; P = 0.004 for FPG; P = 0.046 for D-D). In addition, rs3179089 polymorphism was correlated with low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) serum levels of patients with CAD in both addictive (P = 0.025 for LDL-C; P = 0.001 for TC) and recessive models (P = 0.001 for LDL-C; P = 0.001 for TC). CALM1 expression is associated with development of CAD. CALM1 rs3179089 polymorphism affects CAD susceptibility in males, and blood pressure, blood glucose, blood coagulation and serum lipid of CAD patients.

Association of the CYP1A1 rs4646903 polymorphism with susceptibility and severity of coronary artery disease.

Given the significant physical, mental, and economic problems of coronary artery disease (CAD), it is important for communities to help reduce these costs. The Cytochrome P450 Family 1 Subfamily A Member 1) CYP1A1 (enzyme is known to cause coronary artery disease through various mechanisms. Therefore, it is important to investigate the polymorphisms that affect the activity of this enzyme. After collecting samples from 191 patients with angiographically verified CAD and 191 healthy individuals, genotyping for CYP1A1 rs4646903 polymorphism was carried out. Lipid profile was assessed by conventional colorimetric method. The results showed that the frequency of heterozygous and homozygous mutant genotypes of rs4646903 polymorphism was 36.6% and 5.2% in patients and 20.9% and 2.1% in controls, respectively. The heterozygous genotype (OR=2.24; 95% CI=1.30-3.84, P=0.003), homozygous mutant genotype (OR=3.97; 95% CI=1.05-14.98, P=0.042) and mutant C allele (OR=2.15; 95% CI=1.46-3.15, P<0.001) was significantly associated with CAD risk. Further analysis identified CYP1A1 rs4646903 polymorphism as a significant risk factor for early onset (P= 0.005) but not late onset (P=0.066) CAD. However, the frequency of heterozygous and homozygous mutant genotype of rs4646903 polymorphism did not differ significantly among the CAD patients with various number of stenotic vessel (P>0.05). In conclusion, the rs4646903 polymorphism contributed to the susceptibleness of people to CAD.

Association between HOTAIR lncRNA Polymorphisms and Coronary Artery Disease Susceptibility.

Coronary artery disease (CAD), one of the most frequent causes of mortality, is the most common type of cardiovascular disease. This condition is characterized by the accumulation of plaques in the coronary artery, leading to blockage of blood flow to the heart. The main symptom of CAD is chest pain caused by blockage of the coronary artery and shortness of breath. HOX transcript antisense RNA gene (HOTAIR) is a long non-coding RNA which is well-known as an oncogene involved in various cancers, such as lung, breast, colorectal, and gastric cancer. We selected six single nucleotide polymorphisms, rs4759314 A>G, rs1899663 G>T, rs920778 T>C, rs7958904 G>C, rs12826786 C>T, and rs874945 C>T, for genotype frequency analysis and assessed the frequency of HOTAIR gene polymorphisms in 442 CAD patients and 418 randomly selected control subjects. To analyze the differences between these two populations, we performed a Student’s t-test, adjusted odds ratio (AOR), 95% confidence intervals (CIs), and ANOVA analysis. According to our baseline characteristic analysis, control subjects and CAD patients were significantly different in hypertension and diabetes mellitus. We also found that the rs4759314 A>G, rs1899663 G>T, and rs12826786 C>T genotypes were strongly associated with CAD susceptibility (AA vs. AG+GG: AOR = 0.608, 95% CI = 0.393−0.940, p = 0.025; GG vs. TT: AOR = 2.276, 95% CI = 1.125−4.607, p = 0.022; CC vs. CT+TT: AOR = 1.366, 95% CI = 1.027−1.818, p = 0.032, respectively). Our data also demonstrated that the genotype of HOTAIR polymorphisms, genotype combination, and haplotype analysis affect disease occurrence. Moreover, these polymorphisms are linked to clinical factors that contribute to disease susceptibility. In conclusion, results from our study suggest that HOTAIR polymorphisms may be useful novel biomarkers for diagnosing CAD.

GATA2 regulates the CAD susceptibility gene ADTRP rs6903956 through preferential interaction with the G allele.

Myocardial infarction (MI) is a frequent outcome of coronary artery disease (CAD) and the key factor contributing to worldwide disability and death. Genetic factors contribute to the pathogenesis of CAD/MI, and SNP rs6903956 in the ADTRP gene was first found associated with CAD/MI in the Chinese Han population, which was successfully replicated in other cohorts. However, whether rs6903956 is a functional SNP and its risk mechanism to CAD/MI remains unknown. The ADTRP gene-encoded androgen-dependent TFPI regulating protein regulates vascular endothelial cell function, endothelial-monocyte adhesion, and thrombosis. The allele A of rs6903956, in particular, is associated with lower ADTRP mRNA levels in lymphocytes. In the current study, we found that SNP rs6903956 exhibits allelic differences in transcriptional activity by interacting with GATA2. Also, the A allele conferred a greater risk of CAD and MI, lowered transcriptional activity, and GATA2 binding ability as compared to the G allele. Our findings provide details on how rs6903956 regulates the expression of ADTRP and may provide novel insights into CAD pathology and susceptibility.

Genetic polymorphism of IDOL gene was associated with the susceptibility of coronary artery disease in Han population in Xinjiang, China

BackgroundCoronary artery disease (CAD) is the leading cause of death worldwide. In this study, we aimed to explore whether some genetic variants of the human IDOL gene were associated with CAD among Chinese population in Xinjiang.MethodsWe designed two independent case–control studies. The first one included in the Han population (448 CAD patients and 343 controls), and the second one is the Uygur population (304 CAD patients and 318 controls). We genotyped three SNPs (rs2072783, rs2205796, and rs909562) of the IDOL gene.ResultsOur results revealed that, in the Han female subjects, for rs2205796, the distribution of alleles, dominant model (TT vs. GG + GT) and the additive model (GG + TT vs. GT) showed significant differences between CAD patients and the control subjects (P = 0.048, P = 0.014, and P = 0.032, respectively).ConclusionsThe rs2205796 polymorphism of the IDOL gene is associated with CAD in the Chinese Han female population in Xinjiang, China.

LncRNA H19 rs4929984 Variant is Associated with Coronary Artery Disease Susceptibility in Han Chinese Female Population.

Long non-coding RNAs (lncRNAs) have been reported to play an important role in cardiovascular diseases. The present study aimed to investigate the levels of lncRNA H19 in patients with coronary artery disease (CAD) and the genetic association of lncRNA H19 rs217727 and rs4929984 polymorphisms with CAD susceptibility. We detected an upregulated expression of lncRNA H19 in the peripheral blood of CAD patients compared with healthy controls, and the area under the receiver operating characteristic curve of lncRNA H19 for CAD diagnosis was 0.918. In addition, rs4929984 was associated with the susceptibility of Han Chinese females to CAD, as shown in the additive and dominant models, and the significant association remained after adjusting for age and Bonferroni correction. The A allele carriers of rs4929984 were correlated with females' susceptibility to CAD compared with the C allele, and the A-G haplotype of rs4929984-rs217727 was associated with females' susceptibility to CAD. Furthermore, rs217727 and rs4929984 were associated with the levels of clinicopathological parameters of CAD cases. We suggest that lncRNA H19 has a potential to be a diagnostic biomarker for CAD; rs4929984 polymorphism is associated with females' susceptibility to CAD in the Han Chinese population, and lncRNA H19 variants may influence lipid metabolism, inflammation, and coagulation function of CAD patients.

Protective role of TIRAP functional variant against development of coronary artery disease.

Coronary artery disease (CAD) is the leading cause of sudden death worldwide. Inflammation is proved to be an important player in development of the CAD. Inflammation is directly regulated by the Toll like receptors (TLRs). Susceptibility of CAD is influenced by genetic variations within TLRs and the proteins involved in its signaling cascade. The TIRAP/MAL {TIR domain containing adaptor protein / MyD88 (myeloid differentiation primary response gene 88) adaptor-like} exhibits maximum genetic variations of all adaptor proteins involved in TLR signaling cascade. Susceptibility to a number of diseases can be influenced due to presence of S180L single nucleotide polymorphism (SNP) of TIRAP/MAL. This study was conducted to investigate the functional role of this well characterized S180L polymorphism on susceptibility to CAD among Pakistani patients. A total of 146 Pakistani CAD patients and 147 controls were genotyped by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) and the data was analyzed by using 2-tailed Chi square (x2) test. The p value ≤ 0.05 was considered to be significant.Significantly high frequency of homozygous L180L genotype was observed among healthy subjects as compared to the CAD patients [24 (16%) vs 7 (5%); x2 11.85; p = 0.003]. Moreover, the allele frequency of the minor allele; 180L was observed to be significantly higher among controls than the CAD patients, having same direction of association [156 (53%) vs 131 (45%); OR (95% CI) = 0.7198 (0.520–0.996); p < 0.05).Our results indicate that protective effect of L180L; a coding variant of TIRAP/MAL against CAD is discernible.

Feedback regulation of coronary artery disease susceptibility gene ADTRP and LDL receptors LDLR/CD36/LOX-1 in endothelia cell functions involved in atherosclerosis

A high level of low-density lipoprotein cholesterol (LDL) is one of the most important risk factors for coronary artery disease (CAD), the leading cause of death worldwide. However, a low concentration of LDL may be protective. Genome-wide association studies revealed that variation in ADTRP gene increased the risk of CAD. In this study, we found that a low concentration of oxidized-LDL induced the expression of ADTRP. Further analyses showed that knockdown of the expression of LDL receptor genes LDLR, CD36, or LOX-1 significantly downregulated ADTRP expression, whereas overexpression of LDLR/CD36/LOX-1 markedly increased ADTRP expression through the NF-κB pathway. Like ADTRP, LDLR, CD36 and LOX-1 were all involved in endothelial cell (EC) functions relevant to the initiation of atherosclerosis. Downregulation of LDLR/CD36/LOX-1 promoted monocyte adhesion to ECs and transendothelial migration of monocytes by increasing expression of ICAM-1, VCAM-1, E-selectin and P-selectin, decreased EC proliferation and migration, and increased EC apoptosis, thereby promoting the initiation of atherosclerosis. Opposite effects were observed with the overexpression of ADTRP and LDLR/CD36/LOX-1 in ECs. Interestingly, through the NF-κB and AKT pathways, overexpression of ADTRP significantly upregulated the expression of LDLR, CD36, and LOX-1, and knockdown of ADTRP expression significantly downregulated the expression of LDLR, CD36, and LOX-1. These data suggest that ADTRP and LDL receptors LDLR/CD36/LOX-1 positively regulate each other, and form a positive regulatory loop that regulates endothelial cell functions, thereby providing a potential protective mechanism against atherosclerosis. Our findings provide a new molecular mechanism by which deregulation of ADTRP and LDLR/CD36/LOX-1 promote the development of atherosclerosis and CAD.

The Synergistic Effect of Plasminogen Activator Inhibitor-1 (PAI-1) Polymorphisms and Metabolic Syndrome on Coronary Artery Disease in the Korean Population.

The most common type of cardiovascular disease is coronary artery disease (CAD), in which a plaque builds up inside the coronary arteries that can lead to a complete blockage of blood flow to the heart, resulting in a heart attack. The CAD may be affected by various factors including age, gender, and lipoprotein disposition as well as genetic factors and metabolic syndrome. In this study, we investigated whether three PAI-1 polymorphisms (−844 G > A, −675 4G > 5G, and +43 G > A) and CAD-related clinical parameters are associated with CAD susceptibility. Genotyping of 463 CAD patients and 401 controls was performed using polymerase chain reaction restriction fragment length polymorphism analysis. We report that the 4G5G genotype (crude odds ratio(COR), 1.392; 95% confidence interval (CI), 1.036–1.871; p = 0.028) and dominant model (4G4G vs. 4G5G + 5G5G; COR, 1.401; 95% CI, 1.060–1.850; p = 0.018; adjust odds ratio, 1.371; 95% CI, 1.027–1.831; p = 0.032) of PAI-1 −675 polymorphisms were associated with increased CAD risk. Haplotype and genotype combinations of PAI-1 −675 and +43 polymorphisms show an increased risk of CAD according to alterations of the −675 polymorphism allele or genotype. Moreover, the PAI-1 -675 polymorphisms show a synergistic effect with the metabolic syndrome component of CAD risk. This study suggests that polymorphisms in the PAI-1 genes along with the metabolic syndrome component of CAD can be useful biomarkers for CAD diagnosis and treatment.

A study of associations between CUBN, HNF1A, and LIPC gene polymorphisms and coronary artery disease

The aim of this study was to identify novel genetic markers related to coronary artery disease (CAD) using a whole-exome sequencing (WES) approach and determine any associations between the selected gene polymorphisms and CAD prevalence. CUBN, HNF1A and LIPC gene polymorphisms related to CAD susceptibility were identified using WES screening. Possible associations between the five gene polymorphisms and CAD susceptibility were examined in 452 CAD patients and 421 control subjects. Multivariate logistic regression analyses indicated that the CUBN rs2291521GA and HNF1A rs55783344CT genotypes were associated with CAD (GG vs. GA; adjusted odds ratio [AOR] = 1.530; 95% confidence interval [CI] 1.113–2.103; P = 0.002 and CC vs. CT; AOR = 1.512; 95% CI 1.119–2.045; P = 0.007, respectively). The CUBN rs2291521GA and HNF1A rs55783344CT genotype combinations exhibited a stronger association with CAD risk (AOR = 2.622; 95% CI 1.518–4.526; P = 0.001). Gene-environment combinatorial analyses indicated that the CUBN rs2291521GA, HNF1A rs55783344CT, and LIPC rs17269397AA genotype combination and several clinical factors (fasting blood sugar (FBS), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels) were associated with increased CAD risk. The CUBN rs2291521GA, HNF1A rs55783344CT, and LIPC rs17269397AA genotypes in conjunction with abnormally elevated cholesterol levels increase the risk of developing CAD. This exploratory study suggests that polymorphisms in the CUBN, HNF1A, and LIPC genes can be useful biomarkers for CAD diagnosis and treatment.

Detection of ADTRP in circulation and its role as a novel biomarker for coronary artery disease.

Androgen dependent tissue factor pathway inhibitor regulating protein (ADTRP) is a novel protein associated with coronary artery disease (CAD) susceptibility, and reduced mRNA expression of ADTRP was shown to be associated with increased CAD risk. This study aimed to determine and compare circulating ADTRP levels between CAD patients and controls, and to test the performance of plasma ADTRP as a biomarker for CAD. We measured plasma ADTRP, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and high sensitivity-C reactive protein (hs-CRP) levels in 362 CAD patients, 150 angiographically negative CAD controls, and 83 healthy adults with no known clinical or medical conditions using commercial ELISA. Statistical analyses were performed using receiver operator characteristic (ROC) curves, quantile regression and logistic regression, with adjustments for age, gender, ethnicity and BMI. CAD patients had significantly lower plasma ADTRP levels 1,545 (1,087–2,408) pg/ml as compared to CAD controls 2,259 (1,533–3,778) pg/ml and healthy adults 3,904 (2,732–5,463) pg/ml. Plasma ADTRP outperformed the other three inflammatory biomarkers (TNF-α, IL-6 and hs-CRP) for CAD (Area under ROC curve: 0.67, Odds ratio (OR): 0.907). Our study has shown for the first time that ADTRP is present in circulation, and that plasma ADTRP may be a novel independent biomarker for CAD.

Systematic review and meta-analysis of association of polymorphisms in inflammatory cytokine genes with coronary artery disease.

It has comprehensively beenacknowledged that a genetic contribution, especially in immune inflammatory players, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, are critically involved in the pathophysiology of coronary artery disease (CAD). This meta-analysis study aimed to reach a conclusive understanding of the role of genetic polymorphisms, including IL6 gene C572G (rs1800796) and G174C (rs1800795) as well as TNFA gene G238A (rs361525) and G308A (rs1800629) in susceptibility to CAD. Two major databases, namely MEDLINE and Scopus, were searched to find the studies surveying the mentioned polymorphisms and CAD susceptibility up to July 2020. Association comparison between the polymorphisms and CAD susceptibility were assessed using pooled odds ratio (OR) and their corresponding 95% confidence interval (CI). This meta-analysis study was conducted on 69 papers (73 population studies), comprising 5062 patients and 8446 controls for IL6 gene rs1800796 (17 studies), 13801 patients and 16215 controls for IL6 gene rs1800795 (38 studies), 1439 patients and 2850 controls for TNFA gene rs361525 (5 studies), and 5051 patients and 3958 controls for TNFA gene rs1800629 (13 studies), according to inclusion and exclusion criteria. There were statistically positive association between all genetic comparisons of IL6 gene rs1800795 polymorphism and the CAD risk. Moreover, the recessive model (CC vs. CG + GG) in IL6 gene rs1800796 polymorphism had marginally significant association with decreased risk of CAD. None of the TNFA gene polymorphisms were associated with CAD risk. The meta-analysis revealed the positive association of IL6 gene rs1800795 polymorphism in susceptibility to CAD.