Association Between NAD(P)H Quinone Oxidoreductase 1 (NQO1) Gene Methylation/Expression and Bleeding Incidence Among an Iranian Population Undergoing Warfarin Therapy.

Increased bleeding tendency is a common and challenging complication of warfarin therapy which results in extensive pharmacogenomic studies in order to develop a personalized dosing approach and minimize the risk of related side effects. Here we aimed to explore the potential role of NQO1 gene expression in warfarin response in a group of Iranian patients. We also evaluated the NQO1 promoter methylation and its association with mRNA expression. A total of 87 patients on warfarin therapy including 34 cases with drug-induced bleeding events and 53 matched controls without bleedings were included in the study. The expression of NQO1 was examined by real-time q-PCR and the methylation status of its promoter region was analyzed using methyQESD technique. There was a significant association between the reduced NQO1 gene expression and susceptibility to bleeding before (OR = 1.92, 95% CI = 1.23-3.00, p = 0.004) and following adjustment for hypertriglyceridemia (OR = 2.22, 95% CI = 1.33-3.69, p = 0.002). Furthermore, a medium negative correlation was observed between NQO1 expression and its promoter methylation (r = - 0.382, p = 0.001). The lower expression of NQO1 which partly arises from increased methylation of promoter region, may predispose warfarin treated patients to bleeding events.

Analysis of carbapenemases genes of carbapenem-resistant Klebsiella pneumoniae isolated from Tehran heart center.

Background and Objectives: Emerging of carbapenem-resistant Klebsiella pneumoniae (CRKP) is one of the major concerns among healthcare systems. This study aimed to investigate the antibiotic susceptibility pattern and carbapenemase genes of carbapenemase-producing K. pneumoniae isolates obtained from Iranian hospitalized patients. Materials and Methods: This study was performed on 71 CRKP strains isolated from different clinical specimens collected in Tehran Heart Center (Tehran, Iran). A Modified Hodge test (MHT) was done for the detection of carbapenemase-producing K. pneumoniae. The presence of bla KPC, bla VIM, bla IMP, bla NDM, and bla OXA-48 -type carbapenemases was evaluated by the PCR method. Results: We identified 8.82% (71/805) of K. pneumoniae isolates as CRKP by MHT test. The antibiotic susceptibility indicated that all isolates were resistant to imipenem, meropenem, cefotaxime, ceftazidime, cefepime, ceftriaxone, cephalothin, ciprofloxacin, and augmentin, and then mostly resistant to aztreonam, cefoxitin, gentamicin, and trimethoprim/sulfamethoxazole with 98.6%, 98.6%, 97.2%, and 94.4%, respectively. The lowest resistance was related to amikacin with 46.5% (33/71 isolates). The level of imipenem MIC for all carbapenem-resistant isolates was estimated ≥32 µg/mL. Among positive isolates for carbapenemase genes, the most frequent gene was bla OXA-48. It was found in 48 (67.6%) isolates followed by bla VIM in 28 (39.4%) isolates. bla IMP, bla NDM, and bla KPC genes were identified in 19 (26.8%), 13 (18.3%) and 5 (7.0%) isolates, respectively. These genes were not detected in nine isolates. Conclusion: The relatively high frequency of some carbapenemase genes suggests major concern about the emergence of isolates containing carbapenem resistance genes as a potential health threat.

Predictive Inflammation-related microRNAs for Cardiovascular Events Following Early-Onset Coronary Artery Disease.

BACKGROUND: Early-onset coronary artery disease (EOCAD) increases the risk of major cardiac adverse events (MACE) at the level of safety/effectiveness-related events. Since adverse events affect the quality of life of young patients with EOCAD, MACE prediction is of great importance for improving medical decision-making. AIMS OF THE STUDY: We sought to determine whether the most important inflammation-related microRNAs in atherogenesis could predict MACE among patients with EOCAD. METHODS: This nested case-control study recruited 143 young patients (males ≤45 and females ≤55 years old), selected from a cohort of patients with premature coronary atherosclerosis at a median follow-up period of 64.1 months. Total RNAs were extracted from their peripheral blood mononuclear cells. The expression levels of 18 miRNAs, which are involved in inflammation and atherogenesis, were analyzed via quantitative reverse transcription PCR. RESULTS: A scoring model based on the upregulation of miR-146a_1 and miR-342_1, along with a history of myocardial infarction and the chronic usage of antithrombotic drugs, was able to predict MI/death at the level of safety-related events (higher vs lower risk scores: sHR: 4.61, 95% CI: 1.57-13.57, and p = 0.005). Another prediction model based on the downregulation of miR-145_1, age, and a history of unstable angina was also able to predict revascularization at the level of effectiveness-related events (higher vs lower risk scores: sHR: 2.90, 95% CI: 1.49-5.66, and p = 0.002). CONCLUSIONS: Our results highlighted the role of miRNAs in adverse cardiac events and suggest that miR-146a_1, miR-342_1, and miR-145_1 may be useful biomarkers in predictive and preventive cardiology.

Association of Preoperative Hemoglobin A1c with In-hospital Mortality Following Valvular Heart Surgery.

OBJECTIVE: To determine the association between the preoperative level of hemoglobin A1c (HbA1c) and in-hospital mortality in patients who underwent valvular heart surgery in our center in a retrospective cohort. METHODS: In this retrospective consecutive cohort study, patients with type 2 diabetes mellitus who were referred to our center for elective valvular surgery were enrolled and followed up. The endpoint of this study was in-hospital mortality. Based on the level of HbA1c, patients were dichotomized around a level of 7% into two groups: exposed patients with HbA1c ≥ 7% and unexposed patients with HbA1c < 7%. Then, the study variables were compared between the two groups. RESULTS: Two hundred twenty-four diabetic patients who were candidates for valvular surgery were enrolled; 106 patients (47.3%) had HbA1c < 7%, and 118 patients (52.6%) had HbA1c ≥ 7%. The duration of diabetes was higher in patients with HbA1c ≥ 7% (P=0.007). Thirteen (5.8%) patients died during hospital admission, of which nine patients were in the high HbA1c group. There was no significant difference between the groups regarding in-hospital mortality (P=0.899). Both the unadjusted and adjusted logistic regression models showed that HbA1c was not a predictor for in-hospital mortality (P=0.227 and P=0.388, respectively). CONCLUSION: This study showed no association between preoperative HbA1c levels and in-hospital mortality in candidates for valvular heart surgery.

Association of preoperative hemoglobin a1c with in-hospital mortality following valvular heart surgery

Abstract Objective: To determine the association between the preoperative level of hemoglobin A1c (HbA1c) and in-hospital mortality in patients who underwent valvular heart surgery in our center in a retrospective cohort. Methods: In this retrospective consecutive cohort study, patients with type 2 diabetes mellitus who were referred to our center for elective valvular surgery were enrolled and followed up. The endpoint of this study was in-hospital mortality. Based on the level of HbA1c, patients were dichotomized around a level of 7% into two groups: exposed patients with HbA1c ≥ 7% and unexposed patients with HbA1c < 7%. Then, the study variables were compared between the two groups. Results: Two hundred twenty-four diabetic patients who were candidates for valvular surgery were enrolled; 106 patients (47.3%) had HbA1c < 7%, and 118 patients (52.6%) had HbA1c ≥ 7%. The duration of diabetes was higher in patients with HbA1c ≥ 7% (P=0.007). Thirteen (5.8%) patients died during hospital admission, of which nine patients were in the high HbA1c group. There was no significant difference between the groups regarding in-hospital mortality (P=0.899). Both the unadjusted and adjusted logistic regression models showed that HbA1c was not a predictor for in-hospital mortality (P=0.227 and P=0.388, respectively) Conclusion: This study showed no association between preoperative HbA1c levels and in-hospital mortality in candidates for valvular heart surgery.

The association between CYBA gene C242T variant and risk of metabolic syndrome.

BACKGROUND: Both inflammation and oxidative stress may contribute to pathogenesis of metabolic syndrome (MetS). The C242T polymorphism (rs4673) in the CYBA gene, as the main components of NAD (P) H oxidase, causes inter-individual variability in the enzyme activity. We aimed to investigate the association between this polymorphism with MetS and its components. METHODS: Two hundred nine patients with MetS and 232 controls were included in this study. MetS was defined based on NCEP ATP-III A criteria with some modifications. The C242T polymorphism within CYBA gene was determined by using PCR-based restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: After applying a multiple logistic regression model with adjusting for potential confounders of MetS including, age, sex, body mass index, hypertension, used medications, and diabetes mellitus, C242T polymorphism was found to be associated with the presence of MetS in men but not in the total population or in women. T allele as compared to C allele was associated with decreased odds of MetS in men (adjusted OR = 0.42, 95% CI = 0.24-0.74; P = .003), but not in women (adjusted OR = 1.03, 95% CI = 0.07-1.61; P = .890), or in the total population (adjusted OR = 0.72, 95% CI = 0.51-1.02; P = .063). CONCLUSION: This study shows that T allele of C242T polymorphism in CYBA gene is protective against MetS in Iranian men but not in women. Further cohort studies with larger sample size in subgroups of men and women are required to confirm such association in other racial or ethnic group.

Association between polymorphisms in microRNA seed region and warfarin stable dose.

BACKGROUND: The optimal dose of anticoagulant warfarin varies among patients to achieve the target international normalised ratio. Although genetic variations related to warfarin pharmacokinetics and vitamin K cycle are important factors associated with warfarin dose requirements, these variations do not completely explain the large interindividual variability observed in the most populations, suggesting that additional factors may contribute to this variability. microRNAs have recently been introduced as regulators of drug function genes, and therefore, may be involved in drug responses. In this study, we aimed to evaluate the possible association between variants in the seed region of microRNAs, which target the genes involved in the action of warfarin and warfarin dose requirement. METHODS: 526 samples were collected from Iranian patients. Four selected polymorphisms in the seed region of microRNAs (rs2910164, rs66683138, rs12416605 and rs35770269 in miR-146a, miR-3622a, miR-938 and miR-449c, respectively) were genotyped by PCR-restriction fragment length polymorphism method. RESULTS: rs2910164 C/G in the seed region of miR-146a was associated with warfarin dose requirement (p<0.001); the patients with GG genotype had the higher mean dose of warfarin (40.6 mg/week, compared with 33.9 and 31.8 mg/week for GC and CC genotypes, respectively). The association of other polymorphisms with warfarin dose requirement was not statistically significant. CONCLUSION: rs2910164 C/G in the seed region of miR-146a is associated with warfarin maintenance dose, likely by disrupting interaction between miR-146a and ATP-binding cassette subfamily B member 1 gene, ABCB1. Therefore, this polymorphism may possibly be a potential factor for assessment of warfarin dose requirements.

Integrin Beta-3 Gene Polymorphism and Risk for Myocardial Infarction in Premature Coronary Disease.

BACKGROUND: Contradictory results have been obtained regarding the role of integrin, beta 3 (ITGB3) gene polymorphisms in occurrence of myocardial infarction (MI). OBJECTIVES: We aimed to assess the association between 1565C/T polymorphism of ITGB3 gene and increased risk for acute MI in patients with premature coronary artery disease (CAD). MATERIAL AND METHODS: Our study included 1000 premature CAD patients that classified into two groups with history of MI (n = 461) and without of MI (n = 539). The polymorphism variants in 10% of samples were determined by PCR-RFLP technique and genotyping of the polymorphism in all subjects was conducted by High Resolution Melting method. Given the two conditions of patients residing in Tehran and also faced with their first episode of MI, 640 out of 1000 study samples that had been previously followed-up were assessed in a retrospective cohort phase regarding long-term major adverse cardiac events (MACE). RESULTS: There was no significant difference in the frequency of 1565C/T polymorphism between the MI and non-MI groups. The frequency of wild genotype was 69.2% and 72.2%, the frequency of homozygous genotype was 21.3% and 18.4%, and the frequency of mutant genotype was 9.5% and 9.5%, respectively (P = 0.505). No significant difference was also found in total-MACE free survival rate between the patients with different genotypes of 1565C/T polymorphism in both MI and non-MI group. CONCLUSIONS: The carriage of the 1565C/T polymorphism of ITGB3 gene seems unlikely to be a significant risk factor for the development of MI in Iranian patients with premature CAD.

Association between four microRNA binding site-related polymorphisms and the risk of warfarin-induced bleeding complications.

Bleeding is the most serious complication of warfarin anticoagulation therapy and is known to occur even at patients with therapeutic international normalized ratio (INR) range. Recently, it has been shown that microRNAs play a significant role in pharmacogenetics by regulating genes that are critical for drug function. Interaction between microRNAs and these target genes could be affected by single-nucleotide polymorphisms (SNPs) located in microRNA-binding sites. This study focused on 3'-untranslated region (3'-UTR) SNPs of the genes involved in the warfarin action and the occurrence of bleeding complications in an Iranian population receiving warfarin. A total of 526 patients under warfarin anticoagulation therapy with responding to the therapeutic dose and maintenance of the INR in the range of 2.0-3.5 in three consecutive blood tests were included in the study. Four selected 3'-UTR SNPs (rs12458, rs7294, rs1868774 and rs34669593 located in GATA4, VKORC1, CALU and GGCX genes, respectively) with the potential to disrupt/eliminate or enhance/create microRNA-binding site were genotyped using a simple PCR-based restriction fragment length polymorphism (PCR-RFLP) method. Patients with the rs12458 AT or TT genotypes of the GATA4 gene had a lower risk of bleeding compared to patients with the AA genotype (adjusted OR: 0.478, 95% CI: 0.285-0.802, P= 0.005, OR: 0.416, 95% CI: 0.192-0.902, P= 0.026, respectively). 3'-UTR polymorphisms in other genes were not significantly associated with the risk of bleeding complications. In conclusion, the SNP rs12458A>T in the 3'UTR region of GATA4 is associated with the incidence of warfarin-related bleeding at target range of INR, likely by altering microRNA binding and warfarin metabolism. Further genetics association studies are needed to validate these findings before they can be implemented in clinical settings.

Prothrombin Gene G20210A Variant in Angiographically Documented Patients with Coronary Artery Stenosis.

Background: Studies on the association between the prothrombin G20210A variant and coronary artery disease (CAD) risk are inconclusive. This study aimed to investigate the possible association between the G20210A variant in the prothrombin gene and documented CAD and its severity. Methods: This study enrolled 1460 patients who were consecutively admitted for elective coronary angiography. Via the standard angiographic techniques, coronary angiographies were done and the presence and severity of CAD were determined through the clinical vessel score and the Gensini score. Prothrombin G20210A genotypes were identified using PCR-RFLP. Results: This cross-sectional study was performed on 953 men and 507 women at a mean age of 58.21±10.33 years. The median and the interquartile range for the Gensini score were not statistically significantly different between the wild (GG) and mutant (AA+GA) genotypes (P=0.440). The association between the G20210A polymorphism and the severity of CAD with respect to the vessel score also showed no significant linear trend of higher numbers of diseased vessels (P= 0.765 for the Mantel-Haenszel test of linear trend) in the AA+GA genotype as compared with the GG genotype. Conclusion: Our data failed to confirm the hypothesis that the G20210A variant mutation may be a significant determinant of CAD risk or its severity.

Association between Serum Kalirin Levels and the KALRN gene rs9289231 Polymorphism in Early-Onset Coronary Artery Disease.

Background: Recently, rs9289231 genetic variations of kalirin (KALRN) have been introduced as potential genetic markers for coronary artery disease (CAD). However, the influence of KALRN single-nucleotide polymorphisms (SNPs) on serum kalirin levels has not been investigated in CAD patients so far. Thus, the present study aimed to survey whether SNP T>G (rs9289231) was associated with the risk of early-onset CAD and serum kalirin levels among the study subjects. Methods: The rs9289231 polymorphism of the KALRN was genotyped in 512 subjects (61.5% male, mean age=46.3±7.1 y), comprising 268 subjects with angiographically diagnosed CAD and 244 controls using an HRM assay. Also, the levels of serum kalirin were compared between 133 CAD subjects and 123 controls using a sandwich ELISA assay. Results: The CAD subjects had more frequently GG genotypes than the controls. The odds ratio (OR) remained significant after adjustment for known CAD risk factors (OR=4.13, 95% CI: 2.48-9.10; P<0.001). A significant difference was also observed in that the G allele was more frequent among the CAD subjects. The G allele at the rs9289231 polymorphism was associated with a higher risk of CAD (OR=2.11, 95% CI: 1.27-2.59; P=0.001). The mean kalirin level of the CAD patients was higher than that of the controls (P=0.041). No significant correlation was seen in the different genotypes with serum kalirin levels. Conclusion: The KALRN rs9289231 T>G variant was considerably related with an increased risk of early-onset CAD. High kalirin levels were found in young CAD patients compared to the control subjects, with the levels not affected by the different genotypes of rs9289231.

Non-invasive diagnosis of early-onset coronary artery disease based on cell type-specific gene expression analyses.

A non-invasive diagnostic method based on biomarkers related to endothelial and mononuclear cell dysfunction can provide opportunities for screening and early treatment of atherosclerosis. This study aimed to construct a risk scoring model based on clinical risk factors and molecular markers (lncRNA SENCR and CD markers) at single-cell level for early diagnosis of early-onset coronary artery disease (EOCAD). A single-cell expression analysis was performed on peripheral blood mononuclear cell subsets derived from 253 young individuals (Males ≤45 and Females ≤55 years old) in two training and validation sets using FISH-Flow assay. Concurrent quantifications of intracellular SENCR and surface/intracellular CD31, CD146, CD45 and CD14 in mononuclear cell fractions (Circulating endothelial cell, Monocyte and Lymphocyte) showed a significant reduction in intra-CEC SENCR, increased in intra-monocyte SENCR and also increased surface/intracellular CD146 and CD14 in patients with EOCAD as compared to the controls. Altered biomarkers were combined together as a risk scoring model. The ROC curve analysis on the combination model showed a high-performance in the distinction of our patients with EOCAD and healthy controls. A positive correlation between SENCR and CD14 in monocytes led us to find a binding site corresponding to SENCR and CD14 mRNA interaction. Our study suggested that combination of our molecular and clinical factors can be benefit to early diagnosis of EOCAD. CECs in peripheral blood as the novel approach could reflect molecular alteration in vascular endothelium. Bimodal variation in intracellular SENCR at the single-cell transcriptional level suggests that SENCR has cell-specific function(s) in its epigenetic gene regulation mechanisms.

Association of R279Q and C1562T polymorphisms of matrix metalloproteinase 9 gene and increased risk for myocardial infarction in patients with premature coronary artery disease.

BACKGROUND: A number of matrix metalloproteinase (MMP) gene polymorphisms has been identified which may be probably related to premature myocardial infarction (MI). OBJECTIVE: We assessed the relationship between the two polymorphisms of the MMP9 gene including R279Q and C1562T and occurrence of premature MI. METHODS: The study has two phases including a case-control study as the first phase and cohort study as the second phase. Initially, 1000 patients with premature coronary artery disease were classified into MI and non-MI groups. Genotyping of the polymorphism was conducted by PCRRFLP and high-resolution melting techniques. Given the two conditions of patients residing in Tehran and faced with their first episode of MI, 640 of 1000 study samples previously followed up with a median follow-up time of 45.74 months were assessed in a retrospective cohort phase regarding long-term major adverse cardiac events (MACE). RESULTS: The prevalence of wild, heterozygous, and mutant genotypes of R279Q polymorphism in MI group was 14.5%, 57.3%, and 28.2% and in non-MI group was 36.9%, 38.4%, and 24.7%, respectively, with a considerable difference (P<.001). There was a significant difference in the prevalence of wild, heterozygous, and mutant genotypes of C1562T polymorphisms in MI group (12.4%, 41.2%, and 46.4%, respectively) and in non-MI group (46.8%, 38.6%, and 14.7%, respectively; P<.001). No difference was found in total MACE-free survival rate between genotypes of R279Q and C1562T polymorphisms. CONCLUSION: C1562T and R279Q polymorphisms are associated with the susceptibility to premature MI, but cannot predict long-term cardiac events in these patients.

Association between FTO gene polymorphisms and type 2 diabetes mellitus, serum levels of apelin and androgen hormones among Iranian obese women.

BACKGROUND AND AIMS: Recent studies show that FTO single nucleotide polymorphisms (SNPs) are associated with obesity and type 2 diabetes mellitus (T2DM). On the other hand, many animal models and clinical studies have demonstrated that apelin, an adipocytokine, is related to the obesity and T2DM. Additionally, obese women are at risk of Hyperandrogenemia. So, the aim of this study was to investigate the relationship between FTO variants (rs763967273, rs759031579, rs141115189, rs9926289, rs76804286 and rs9939609) with T2DM, serum apelin and androgenic hormones in Iranian obese women. SUBJECTS AND METHODS: 197 obese women (123 women with T2DM and 74 women as healthy control) were participated in this study. Anthropometrical and biochemical characteristics were measured. Serum apelin and androgen hormones levels were determined in 66 subjects consisting of 33 cases and 33 controls. PCR were carried out and subsequently, the PCR production was genotyped by Sanger sequencing assay. RESULTS: Our observations showed that all SNPs are related to T2DM. The rs9926289 FTO variant had a strong association with serum apelin and dehydroepiandrosterone-sulfate levels (P=0.04 and P=0.03, respectively) among SNPs. In addition, apelin and androgenic hormones were correlated with T2DM. Two polymorphisms including rs9939609 and rs9926289 had a strong Linkage disequilibrium (r2=1). CONCLUSION: FTO variants not only were associated with T2DM, but also some variants had a strong association with apelin and androgenic hormones profile.

Association between the Hepatic Lipase Promoter Region Polymorphism (-514 C/T) and the Presence and Severity of Premature Coronary Artery Disease.

Background: Hepatic lipase (HL) plays a crucial role in lipid metabolism, but there is debate about whether HL acts in a more pro- or more anti-atherogenic fashion. We aimed to examine the relationship between the -514 C/T polymorphism within the HL gene (LIPC) and the risk of angiographically determined premature coronary artery disease (CAD). Methods: Four hundred seventy-one patients with newly diagnosed angiographically documented (≥ 50% luminal stenosis of any coronary vessel) premature CAD were compared to 503 controls (subjects with no luminal stenosis in coronary arteries). A real-time polymerase chain reaction and high-resolution melting analysis was used to distinguish between the genotypes. Results: There was no significant difference in the distribution of -514 C/T genotypes between the 2 groups in the whole population or in the men, but the examined polymorphism was found to be associated with the presence of CAD in the women (p value = 0.029). After the application of a multiple logistic regression model, the minor T allele of the LIPC gene was not found to be independently associated with the presence of CAD either in the total population (adjusted OR = 0.97, 95% CI = 0.75-1.25; p value = 0.807) or in the women (adjusted OR = 0.91, 95% CI = 0.59-1.40; p value = 0.650) and in the men (adjusted OR = 1.15, 95% CI = 0.81-1.64; p value = 0.437) separately. Conclusion: Our findings suggest that there is no relationship between the LIPC -514 C/T and the risk of premature CAD or its severity in patients undergoing coronary angiography.

C1019T Polymorphism in the Connexin 37 Gene and Myocardial Infarction Risk in Premature Coronary Artery Disease.

Background: The C1019T polymorphism of the connexin-37 (GJA4) gene is a single-nucleotide polymorphisms involved in atherosclerotic plaque rupture and atherosclerosis predisposition. We examined the association between the C1019T polymorphism of the GJA4 gene and the occurrence of myocardial infarction (MI) in patients with premature coronary artery disease (CAD). Methods: Our study recruited 1000 patients with the final diagnosis of premature CAD and classified them into 2 groups: with a history of MI (n = 461) and without it (n = 539). The polymorphism variants were determined via the PCR-RFLP, and then genotyping was conducted through the high-resolution melting method. From a total of 1000 patients, 554 patients, who had been previously followed-up with a median follow-up time of 45.74 months vis-à-vis long-term major adverse cardiac events, were enrolled in this retrospective cohort phase. Results: The frequencies of the wild, heterozygous, and mutant genotypes of the C1019T polymorphism were 54.0%, 40.6%, and 5.4% in the MI group and 49.2%, 43.2%, and 7.6% in the non-MI group (p value = 0.187). After adjustment for the baseline covariates, no difference was found between the MI and non-MI groups apropos the frequency of the heterozygous genotype (p value = 0.625) and the mutant genotype (p value = 0.452). Regarding the level of human connexin-37, the serum level of this marker was not different between the MI and non-MI groups. Conclusion: The C1019T polymorphism of the GJA4 gene may not be useful for predicting the occurrence of MI in patients with premature CAD. The presence of this polymorphism in such patients may also have a low value for predicting long-term CAD complications.

The impact of vascular endothelial growth factor +405 C/G polymorphism on long-term outcome and severity of coronary artery disease.

BACKGROUND: The association between genetic variations of vascular endothelial growth factor (VEGF) gene and the risk for atherosclerosis has been hypothesized. We aimed to assess the relationship between rs2010963 (+405 C/G) polymorphism and presence, severity, and outcome of coronary artery disease (CAD) in an Iranian cohort. METHODS: Genotyping of VEGF rs2010963 polymorphism was performed on 520 individuals, comprising 347 patients with documented coronary artery disease based on angiography report and 173 individuals with normal coronary arteries, using the TaqMan real-time PCR method. In final, 484 subjects were followed up over a 5-year period for cardiovascular-related outcomes. RESULTS: C allele of VEGF rs2010963 polymorphism was related to increase risk for CAD and also slightly to 5-year cardiovascular mortality. The 5-year survival in C and G allele subgroups were 92.3% and 94.3% in CAD group and 95.7% and 98.0% in non-CAD group, respectively. CONCLUSIONS: Vascular endothelial growth factor rs2010963 polymorphism may be associated with the presence of CAD and its long-term survival, but not with its severity. To the best of our knowledge, this is the first report of genetic association between rs2010963 SNP and CAD-related death. It can be thus suggested that rs2010963 VEGF gene can be considered as a genetic risk predictor for CAD and its outcomes.

NQO1 C609T Polymorphism is Associated with Coronary Artery Disease in a Gender-Dependent Manner.

Findings on the association of NQO1 C609T polymorphism in the NQO1 gene and cardiovascular disease susceptibility are controversial. The objective of the current study was to examine the relationship between this polymorphism and the presence and severity of angiographically determined coronary artery disease (CAD). One-hundred and forty-five patients with newly diagnosed angiographically documented CAD (≥50 % luminal stenosis of any coronary vessel) as case group were compared to 139 controls (subjects with no luminal stenosis at coronary arteries). The presence of C609T polymorphism was analyzed using polymerase chain reaction-based restriction fragment length polymorphism. Among total population, those with combined CT/TT (T allele carrier) genotype showed a trend toward lower odds of CAD compared to those with CC (wild type) genotype, but it did not reach a statistically significant level (p = 0.061). When data were analyzed separately for men or women, CT + TT group as compared to CC genotype was associated with decreased odds of CAD in women (adjusted OR 0.4, 95 % CI 0.2-0.9; p = 0.043), but not in men (adjusted OR 0.8, 95 % CI 0.3-1.9; p = 0.612). The C609T polymorphism within NQO1 is independently associated with CAD in women, but no association was observed in whole study population or in men.

Gene polymorphisms and the risk of warfarin-induced bleeding complications at therapeutic international normalized ratio (INR).

BACKGROUND: Bleeding episodes commonly occur in patients on warfarin treatment even in those within therapeutic range of international normalized ratio (INR). The objective of this study was to investigate the effects of the 8 examined polymorphisms on the risk of bleeding complications in a sample of Iranian patients. METHODS: A total of 552 warfarin treated patients who maintained on a target INR level of 2.0-3.5 for at least three consecutive intervals were enrolled from those attended our anticoagulation clinics. Ninety-two bleeding events were observed in 87 patients. The presences of the examined polymorphisms were analyzed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). RESULTS: Patients with the T allele in NQO1*2 (CT or TT genotypes) had a higher risk of bleeding than patients with the CC genotype (adjusted OR: 2.25, 95% CI: 1.37 to 3.70, P=0.001). Those who were carriers of CYP2C9 one-variant haplotypes (*1/*2 or *1/*3) were also found to be associated with the higher risk of bleeding events. Compared to reference group (*1/*1), the odds of bleeding increased for carriers of one variant allele (*1/*2 or *1/*3) (adjusted OR: 1.75, 95% CI: 1.03 to 2.97, P=0.039). Variant VKORC1, Factor VII, and EPHX1 genotypes were not significantly associated with the risk of bleeding events. CONCLUSION: The SNP C609T within NQO1 and haplotypes of CYP2C9 (1*2 or 1*3) are independently associated to bleeding complications of warfarin at normal INR. Further studies are required to confirm such associations in diverse racial and ethnic populations.

Association of KALRN, ADIPOQ, and FTO gene polymorphism in type 2 diabetic patients with coronary artery disease: possible predisposing markers.

OBJECTIVES: Recently, several genes have been introduced as potential genetic markers for diabetes mellitus and coronary artery diseases (CAD). METHODS: In this case-control study, the associations of rs2241766 T/G of ADIPOQ, rs9289231 T/G of KALRN, and rs9939609 A/T of FTO polymorphisms with genetic susceptibility to CAD in type 2 diabetic (T2D) patients were investigated. A total of 224 T2D patients undergoing coronary angiography were randomly recruited into the study. Of the total diabetic patients, 152 were also diagnosed with CAD, whereas the rest were control participants. Genotyping of single-nucleotide polymorphisms was performed by high-resolution melting analysis. RESULTS: Genotype analysis showed that the minor allele (G) frequency of rs2241766 ADIPOQ was statistically significant in the CAD group compared with the control group [odds ratio (OR), 2.779; 95% confidence interval (CI), 1.403-5.504; P=0.003]. Also, it was found that the minor allele (G) frequency of rs9289231 KALRN was significantly associated with the risk of CAD (OR, 2.098; 95% CI, 1.096-4.017; P=0.025). In addition, no significant association was observed between the minor allele (A) of the FTO rs9939609 polymorphism and CAD (OR, 1.088; 95% CI, 0.578-2.015; P=0.788). It is speculated that the GG genotype and the G allele of the rs9289231 polymorphism of KALRN and the rs224766 polymorphism of ADIPOQ genes may be considered genetic risk factors for CAD in T2D patients and genetic variations of these genes may play a major role in the process of these disorders. CONCLUSION: Our case-control study in the Iranian population suggested a possible association between the mentioned single-nucleotide polymorphisms and CAD in T2D patients. However, further replication studies and comprehensive meta-analyses are required.