Association Study of the ATP - Binding Cassette Transporter A1 (ABCA1) Rs2230806 Genetic Variation with Lipid Profile and Coronary Artery Disease Risk in an Iranian Population

BACKGROUND: ATP - binding cassette transporter A1 (ABCA1) plays essential roles in the biogenesis of high -density lipoprotein - cholesterol. Variations in the ABCA1 gene may influence the risk of coronary artery disease (CAD).AIM: Present study aimed to investigate the association of rs2230806 (R219K) polymorphism of ABCA1 gene with the development and severity of CAD in an Iranian population.MATERIALS AND METHODS: Our study population consisted of 100 patients with angiographically confirmed CAD and 100 controls. The genotyping of R219K mutation of ABCA1 gene was determined by PCR - RFLP method. Lipid profile was determined using routine colourimetric assays. Statistical analysis was done by SPSS - 16.RESULTS: The genotypic (P = 0.024) and allelic (P = 0.001) distribution of the ABCA1 R219K polymorphism were significantly different between the two groups. In a univariate analysis (with genotype RR as the reference), the RK genotype (OR = 0.46, 95%CI = 0.25-0.86, P = 0.020) and KK genotype (OR = 0.27, 95%CI = 0.11 – 0.66, P = 0.005) was significantly associated with a decreased risk of CAD. A multiple logistic regression analysis revealed that smoking (0.008), diabetes (P = 0.023), triglyceride (P = 0.001), HDL - cholesterol (P = 0.002) and ABCA1 KK genotype (P = 0.009) were significantly and independently associated with the risk of CAD. The association between different genotypes of R219K polymorphism with lipid profile was not significant in both groups (P > 0.05). The R219K polymorphism was significantly associated with severity of CAD (P < 0.05).CONCLUSION: The carriage of K allele of ABCA1 R219K polymorphism has a protective effect on CAD risk and correlates with a decreased severity of CAD. This protective effect seems to be mediated independently of plasma lipid levels

The C-565T Polymorphism (rs2422493) of the ATP-binding Cassette Transporter A1 Gene Contributes to the Development and Severity of Coronary Artery Disease in an Iranian Population

Objectives: ATP-binding cassette transporter A1 (ABCA1) plays a pivotal role in reverse cholesterol transport from peripheral tissues back to the liver. Abnormalities in ABCA1 function may lead to dyslipidemia and coronary artery disease (CAD). We investigated the role of C-565T (rs2422493) promoter polymorphism of ABCA1 gene in the development and severity of CAD in an Iranian subpopulation. Methods: Our study population consisted of 110 angiographically-confirmed CAD patients and 110 matched controls. The severity of CAD was expressed based on the number of stenotic vessels. Genotyping of C-565T promoter polymorphism was performed using the polymerase chain reaction followed by restriction fragments length polymorphism analysis methods. Lipid profile was determined by routine colorimetric methods. Results: The distribution of ABCA1 C-565T genotypes (p = 0.035) and alleles (p = 0.017) was significantly different between the CAD and control groups. In univariate analysis (with genotype CC as reference), the TT genotype was significantly associated with an increased risk of CAD (odds ratio = 3.83; 95% confidence interval: 1.29–11.30, p = 0.014), but the CT genotype was not (p = 0.321). A multiple binary logistic regression analysis revealed that smoking, hypertension, triglyceride, cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and ABCA1 C-565T dominant genotype were significant and independent risk factors for CAD development (p 0.050). Conclusions: Our study indicated that ABCA1 C-565T polymorphism is a significant risk factor for development and severity of CAD in our population

The Correlation of Cardiac and Hepatic Hemosiderosis as Measured by T2*MRI Technique with Ferritin Levels and Hemochromatosis Gene Mutations in Iranian Patients with Beta Thalassemia Major

Objectives: Organ-specific hemosiderosis and iron overload complications are more serious and more frequent in some patients with beta thalassemia major (BTM) compared with others. We investigated whether coinheritance of HFE H63D or C282Y gene mutations in patients with BTM contributes to the phenotypic variation of iron overload complications and assessed the correlation of cardiac and hepatic hemosiderosis with plasma ferritin levels. Methods: We studied 60 patients with BTM with a mean age of 17.5±9.1 years from the Northwest of Iran. HFE gene mutations were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method. Cardiac and hepatic hemosiderosis was assessed using T2*magnetic resonance imaging (MRI). Ferritin levels were measured using the enzyme immunoassay method. Results: Ferritin levels showed a strong inverse correlation with hepatic T2*MRI values (r = -0.631, p = 0.001) but a poor correlation with cardiac T2*MRI values (r = -0.297, p = 0.044). The correlation between cardiac T2*MRI values and hepatic T2*MRI values was poor and insignificant (r = 0.287, p = 0.058). Genotype and allele distribution of HFE H63D and C282Y mutation did not differ significantly between patients with and without hepatic or cardiac hemosiderosis (p > 0.050). However, carriers of HFE 63D allele had significantly higher ferritin levels compared with non-carriers (1 903±993 vs. 992±683, p < 0.001). Conclusions: Cardiac T2*MRI values showed a poor correlation with hepatic T2*MRI values and ferritin levels. Accurate assessment of cardiac iron overload in patients with BTM can only be done using the T2*MRI technique. Additionally, HFE H63D is a significant determinant factor for elevated ferritin levels in BTM patients

Assessment of the role of plasma nitric oxide levels, T-786C genetic polymorphism, and gene expression levels of endothelial nitric oxide synthase in the development of coronary artery disease

Background: Reduced bioavailability of nitric oxide (NO) and the T-786C polymorphism of endothelial nitric oxide synthase (eNOS) gene have been reported as risk factors for the development of coronary artery disease (CAD) with conflicting results. We investigated the association of plasma NO levels, T-786C genetic polymorphism, and gene expression levels of eNOS with CAD risk in an Iranian subpopulation. Materials and Methods: Studied population included 100 patients with angiographically verified CAD and 100 ethnically matched controls. Analysis of T-786C genetic polymorphism and gene expression levels of eNOS was conducted by polymerase chain reaction (PCR) restriction fragment length polymorphism and real-time reverse transcription-PCR methods, respectively. Plasma levels of NO were measured using Griess method. Results: The CC genotype distribution (15% vs. 6%, P = 0.011) and minor C allele frequency (36.5% vs. 21.5%, P = 0.001) of eNOS T-786C polymorphism differed significantly between CAD patients and control. Furthermore, eNOS T-786C polymorphism was more common among smoker than nonsmoker CAD patients (27.7% vs. 7.8%, P = 0.044). The association of the eNOS T-786C polymorphism with the severity of CAD (number of diseased vessel) was significant (P < 0.05). The gene expression levels of eNOS were significantly lower in the heterozygote (0.49 ± 0.1, P = 0.023) and mutant homozygote (0.36 ± 0.09, P = 0.011) genotypes than that of wild-type genotype (P < 0.05). In addition, NO levels were significantly lower in CAD patients compared with control subjects (42.62 ± 12.26 vs. 55.48 ± 16.57, P = 0.002) and showed intergenotypic variation in the CAD patients. Conclusion: Our study indicated that reduced NO levels and eNOS T-786C genetic polymorphism are significant risk factors for the development and severity of CAD in the Iranian population

Plasma concentration, genetic variation, and gene expression levels of matrix metalloproteinase 9 in Iranian patients with coronary artery disease

Background: Matrix metalloproteinase 9 (MMP9) -1562C>T (rs3918242) polymorphism has been proposed as a risk factor for coronary artery disease (CAD) with conflicting results. The aim of the present study was to investigate the association of -1562C>T genetic polymorphism, gene expression and circulating levels of MMP9 with CAD risk in an Iranian subpopulation in in Zanjan City. Materials and Methods: This was a retrospective case–control study we investigated retrospectively 100 patients with angiographically verified CAD and 100 matched controls. Genotyping of -1562C>T polymorphism was done by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Gene expression levels and circulating levels of MMP9 was determined by real-time reverse transcription-PCR and enzyme immunoassay method, respectively. Statistical analysis was done using Student's t-test or Chi-square test by SPSS 16 software. Results: The mean circulating levels of MMP9 were significantly higher in CAD Group than control group (P = 0.002). Mean plasma levels of MMP9 were also significantly higher in triple vessel stenosis patients than double vessel or single vessel stenosis patients (P T polymorphism (P = 0.002, P = 0.01, respectively). However, genotype and allele frequencies of MMP9 -1562C>T polymorphism were similar between CAD patients and controls (P > 0.05). Additionally, the -1562C>T polymorphism of MMP9 gene didn't increase the risk of CAD in dominant (P = 0.537) or recessive (P = 0.249) genetic models. Conclusion: Our study demonstrated that circulating levels of MMP9 but not -1562C>T polymorphism of MMP9 gene may be a risk factor for development and severity of CAD in an Iranian subpopulation in Zanjan

Cardioprotective effects of mebudipine in a rat model of doxorubicin-induced heart failure

Background: Mebudipine, a dihydropyridine calcium-channel blocker (CCB), shows greater time- and voltage-dependent inhibitory effects than nifedipine. Its significant negative chronotropic effects without having considerable negative inotropic properties may make it a suitable candidate for the pharmacotherapy of heart failure (HF). This study aimed to investigate the possible beneficial action of mebudipine in a rat model of HF. Methods: The present study carried out in the Department of Pharmacology at the Iran University of Medical Sciences during the years of 2009-2011. An experimental model of HF was induced in male Wistar rats using doxorubicin (DOX). The rats were divided into five groups with seven animals in each group: normal control group, DOX-induced HF control groups, and treatment groups. The animals were administered DOX for 15 days. A consistent deterioration occurred after a four-week rest period. The animals were then treated with intraperitoneal mebudipine (0.5 mg/kg) and intraperitoneal amlodipine (0.35 mg/kg), as well as an equal volume of distilled water for 15 days. The plasma levels of big endothelin-1 (BET-1), creatine kinase-myocardial band (CKMB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), as well as the clinical status (heart rate and blood pressure), were assessed before and after treatment. Statistical analysis was performed with SPSS software using parametric and nonparametric ANOVA. Results: Mebudipine and amlodipine reversed the increased plasma BET-1 values in the treated animals when compared with the HF control group (0.103 and 0.112 vs 0.231 pg/ mL, respectively). The increased plasma levels of AST, ALT, CK-MB, and LDH were also reversed in the HF animals that received mebudipine or amlodipine. Conclusion: The administration of mebudipine to HF animals, akin to amlodipine, palliated the clinical and biochemical signs of the disease in the present study. The abstract was presented in the Iranian Congress of Physiology and Pharmacology as a poster and published in the Scientific Information Database as a supplement (2015; Vol 22)

Evaluation of the Role of -137G/C Single Nucleotide Polymorphism (rs187238) and Gene Expression Levels of the IL-18 in Patients with Coronary Artery Disease

Objectives: Interleukin-18 (IL-18) is a proinflammatory and proatherogenic cytokine, and its genetic variations may contribute to the development of coronary artery disease (CAD). We sought to investigate the role of -137G/C polymorphism and gene expression levels of IL-18 in patients with CAD. Methods: The study population included 100 patients with angiographically proven CAD and 100 matched controls. Total RNA and DNA were extracted from leukocytes using appropriate kits. The genotype of -137G/C polymorphism and gene expression level of IL-18 was determined using allele-specific polymerase chain reaction (PCR) and real-time (RT)-PCR assay, respectively. Results: The genotypic and allelic distribution of IL-18 -137G/C polymorphism was not significantly different between the two groups (p > 0.050). Moreover, the -137G/C polymorphism did not increase the risk of CAD in dominant and recessive genetic models (p > 0.050). However, subgroup analysis of CAD patients revealed that the IL-18 -137G/C polymorphism was significantly associated with increased risk of CAD in hypertensive patients (odds ratio (OR) = 7.51; 95% confidence interval (CI): 1.24–25.17; p = 0.019) and smokers (OR = 4.90; 95% CI: 1.21–19.70; p = 0.031) but not in the diabetic subpopulation (p = 0.261). The genotype distribution of IL-18 -137G/C genetic polymorphism was significantly different among patients with one, two, and three stenotic vessels (p < 0.050). The gene expression level of IL-18 was significantly higher in the CAD group than the control group (p < 0.001). Moreover, the carriers of CC genotype had significantly lower gene expression levels of IL-18 than carriers of GG genotype (p < 0.050).Conclusions: The -137G/C polymorphism of IL-18 may be associated with the CAD risk in hypertensive and smoker subgroup of CAD patients. The -137G/C polymorphism seems to play an important role in determining the severity of CAD. Increased IL-18 gene expression level is a significant risk factor for the development of CAD. The CC genotype of -137G/C polymorphism is associated with lower IL-18 gene expression levels

Methylenetetrahydrofolate reductase C677T mutation and risk of retinal vein thrombosis

Background: Elevated plasma homocysteine (Hcy) level has been established as a significant risk factor for venous thrombosis and cardiovascular disease. Homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation has been associated with elevated plasma Hcy concentration and may contribute to retinal vein thrombosis (RVT) development. The aim of the present study was to investigate whether the hyperhomocysteinemia and/or homozygosity for the MTHFR C677T mutation are associated with an increased risk for RVT. Materials and Methods: Our study population consisted of 73 consecutive patients (50-78 years old) with RVT and 73 control subjects (51-80 years old), matched for age and sex. Genotyping for the MTHFR C677T mutation was performed by polymerase chain reaction-restriction fragment length polymorphism technique and Hcy level was determined by an enzyme immunoassay kit. Results: The prevalence of 677TT genotype was higher in patients than control subjects, but the difference in frequency didn′t reach a significant value (P = 0.07). The frequency of the 677T allele was 26% and 21.2% in patients and controls, respectively and did not differ significantly between the two groups (odds ratio = 1.3, 95% confidence interval (0.75-2.24), P = 0.33). Fasting plasma total Hcy level was significantly higher in patients than controls (P = 0.001). Conclusion: Our study demonstrated that hyperhomocysteinemia, but not the MTHFR C677T mutation, is associated with RVT