Endothelin-converting Enzyme-1b Genetic Variants Increase the Risk of Coronary Artery Ectasia.

Coronary artery ectasia (CAE), defined as a 1.5-fold or greater enlargement of a coronary artery segment compared to the adjacent normal coronary artery, is frequently associated with atherosclerotic coronary artery disease (CAD). Membrane-bound endothelin converting enzyme-1 (ECE-1) is involved in the maturation process of the most potent vasoconstrictor ET-1. Polymorphisms in the endothelin (ET) gene family have been shown associated with the development of atherosclerosis. This study aims to investigate the effects of rs213045 and rs2038089 polymorphisms in the ECE-1 gene which have been previously shown to be associated with atherosclerosis and hypertension (HT), in CAE patients. Ninety-six CAE and 175 patients with normal coronary arteries were included in the study. ECE-1b gene variations rs213045 and rs2038089 were determined by real-time PCR. The frequencies of rs213045 C > A (C338A) CC genotype (60.4% vs. 35.4%, p < 0.001) and rs2038089 T > C T allele (64.58% vs. 35.42%, p = 0.017) were higher in the CAE group compared to the control group. The multivariate regression analysis showed that the ECE-1b rs213045 CC genotype (p = 0.001), rs2038089 T allele (p = 0.017), and hypercholesterolemia (HC) (p = 0.001) are risk factors for CAE. Moreover, in nondiabetic individuals of the CAE and control groups, it was observed that the rs213045 CC genotype (p < 0.001), and rs2038089 T allele (p = 0.003) were a risk factor for CAE, but this relationship was not found in the diabetic subgroups of the study groups (p > 0.05). These results show that ECE-1b polymorphisms may be associated with the risk of CAE and this relationship may change according to the presence of type II diabetes.

Receptor for advanced glycation end products polymorphisms in coronary artery ectasia.

BACKGROUND: Although the implication of receptor of advanced glycation endproducts (RAGE) has been reported in coronary artery disease, its roles in coronary artery ectasia (CAE) have remained undetermined. Furthermore, the effect of RAGE polymorfisms were not well-defined in scope of soluble RAGE (sRAGE) levels. Thus, we aimed to investigate the influence of the functional polymorphisms of RAGE -374T > A (rs1800624) and G82S (rs2070600) in CAE development. METHODS: This prospective observational study was conducted in 2 groups selected of 2452 patients who underwent elective coronary angiography (CAG) for evaluation after positive noninvasive heart tests. Group-I included 98 patients with non-obstructive coronary artery disease and CAE, and Group-II (control) included 100 patients with normal coronary arteries. SNPs were genotyped by real-time PCR using Taqman® genotyping assay. Serum sRAGE and soluble lectin-like oxidized receptor-1 (sOLR1) were assayed by ELISA and serum lipids were measured enzymatically. RESULTS: The frequencies of the RAGE -374A allele and -374AA genotype were significantly higher in CAE patients compared to controls (p < 0.001). sRAGE levels were not different between study groups, while sOLR1 levels were elevated in CAE (p = 0.004). In controls without systemic disease, -374A allele was associated with low sRAGE levels (p < 0.05), but this association was not significant in controls with HT. Similarly, sRAGE levels of CAE patients with both HT and T2DM were higher than those no systemic disease (p = 0.02). The -374A allele was also associated with younger patient age and higher platelet count in the CAE group in both total and subgroup analyses. In the correlation analyses, the -374A allele was also negatively correlated with age and positively correlated with Plt in all of these CAE groups. In the total CAE group, sRAGE levels also showed a positive correlation with age and a negative correlation with HDL-cholesterol levels. On the other hand, a negative correlation was observed between sRAGE and Plt in the total, hypertensive and no systemic disease control subgroups. Multivariate logistic regression analysis confirmed that the -374A allele (p < 0.001), hyperlipidemia (p < 0.05), and high sOLR1 level (p < 0.05) are risk factors for CAE. ROC curve analysis shows that RAGE -374A allele has AUC of 0.713 (sensitivity: 83.7 %, specificity: 59.0 %), which is higher than HLD (sensitivity: 59.2 %, specificity: 69.0 %), HT (sensitivity: 62.4 %, specificity: 61.1 %) and high sOLR1 level (≥0.67 ng/ml)) (sensitivity: 59.8 %, specificity: 58.5 %). CONCLUSION: Beside the demonstration of the relationship between -374A allele and increased risk of CAE for the first time, our results indicate that antihypertensive and antidiabetic treatment in CAE patients causes an increase in sRAGE levels. The lack of an association between the expected -374A allele and low sRAGE levels in total CAE group was attributed to the high proportion of hypertensive patients and hence to antihypertensive treatment. Moreover, the RAGE -374A allele is associated with younger age at CAE and higher Plt, suggesting that -374A may also be associated with platelet activation, which plays a role in the pathogenesis of CAE. However, our data need to be confirmed in a large study for definitive conclusions.

Unusual effects of PCSK9 E670G (rs505151) variation in patients with in-stent restenosis: Variable effects on restenosis risk according to concomitant chronic conditions.

Recent reports showing that neo-atherosclerosis formation in stented coronary artery is characterized by the accumulation of lipid-laden macrophages within the neointima has strengthened the possibility that elevated low-density lipoprotein (LDL)-cholesterol may be a risk factor for in-stent restenosis (ISR). Protein Convertase Subtilisin/Kexin-9 (PCSK9) protein plays an important role in cholesterol metabolism by degrading of LDL receptors. The gain-of-function E670G (rs505151) mutation of the PCSK9 gene is a well-known genetic risk factor for hypercholesterolemia. This study evaluated for the first time the association of the E670G variation with the serum lipids, PCSK9 levels and concomitant diseases on the ISR risk. The study included 109 ISR, and 82 Non-ISR patients, based on the results of coronary angiography. Genotypes were determined using the real-time PCR and serum PCSK9 levels were measured by ELISA technique. The rare G allele of PCSK9 E670G (p < 0.05), hyperlipidemia (HL) (p < 0.001), and type 2 diabetes (T2DM) (p < 0.01) were associated with increased risk for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR (p < 0.001), while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. In addition, diabetic ISRs had higher serum PCSK9 levels (p < 0.05) and the E670G-AA genotype was associated with increased levels of diabetes markers. Our results indicated that the unusual effects of both G allele and AA genotype of the PCSK9 E670G variation may be involved in the risk of ISR in association with concomitant metabolic diseases.

This study evaluated the association of the Protein Convertase Subtilisin/Kexin-9 (PCSK9) E670G mutation with the serum lipids, PCSK9 levels and concomitant diseases on the in-stent restenosis (ISR) risk. The E670G-G allele, hyperlipidemia, and type 2 diabetes (T2DM) were found risk factors for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR, while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. Our results indicated that the unusual effects of both genotypes of the E670G that may be involved in the ISR risk in association with concomitant diseases.

Comparative effects of the antioxidant glutathione with metformin and Diane-35 on hormonal, metabolic, and inflammatory indicators in a DHEA-induced PCOS rat model.

OBJECTIVE: Comparison of hormonal, metabolic and inflammatory markers of glutathione with metformin and Diane-35 in a rat model of PCOS induced by dehydroepiandrosterone. METHODS: Twenty-five female rats were randomized into four groups. Group 1 was administered a subcutaneous dose of 0.2 ml saline/day. Group 2 was given 0.2 ml of 1% carboxymethyl cellulose (CMC)/day orally for 28 days. A PCOS model was established with DHEA in rats. Group 3 was given 4.5 mg/kg/day of Diane-35 orally dissolved in 1% CMC for 28 days. Group 4 was given 300 mg/kg/day of metformin orally dissolved in 1 ml of saline for 28 days, and Group 5 was administered 100 mg/kg of glutathione intraperitoneally on days 35, 42, and 49. On day 56, the rats were sacrificed. Serum markers and follicle count were examined. RESULTS: Serum IL-6, hs-CRP, insulin, testosterone, SHBG, and MDA values were significantly lower in the glutathione group than in the PCOS group (p = 0.0006, p = 0.023, p = 0.0082, p = 0.0007, p = 0.0048, and p < 0.0001, respectively).The number of all follicles was similar between the control and glutathione groups (p < 0.05). When we compared the other groups with the PCOS group, the number of primary, secondary, atretic, and cystic follicles was significantly lower in the metformin and glutathione groups. The number of primordial and antral follicles was significantly higher than in the PCOS group. CONCLUSIONS: Glutathione plays anti-inflammatory and antioxidant roles, similar to metformin, by lowering serum IL-6, insulin, testosterone, CRP, and MDA levels; decreasing atretic/cystic follicle count; and improving antral follicle count and folliculogenesis in PCOS patients.

Investigation of Scavenger Receptor Class B Type I gene variants in patients with coronary heart disease with a history of early myocardial infarction.

OBJECTIVE: The scavenger receptor class B type 1 (SR-BI, SCARB1), which is a high-density lipoprotein (HDL) receptor that mediates selective cholesteryl ester uptake, plays an important role in reverse cholesterol transport. This study investigated the distribution of polymorphic variants of the SR-BI gene in patients with coronary heart disease (CHD) with a history of early myocardial infarction (MI) at an early age and their effects on their serum lipid levels. METHODS: SR-BI rs5888(T>C), rs4238001(C>T), and rs10846744(G>C) were analyzed in 100 male patients with CHD with a history of MI (MI+) who were younger than 50 years and 89 male control subjects without MI history (MI-) using real-time polymerase chain reaction (PCR) and mutant-allele-specific PCR techniques. RESULTS: SR-BI rs4238001 common-CC genotype was found to be more frequent in patients with MI+ than in control subjects (MI-; odds ratio 4.046, p<0.001). The rs10846744 rare-C allele showed a significant association with increased total cholesterol (p=0.014) and triglyceride (p=0.009) levels in the MI+ CHD group. Logistic regression analysis confirmed that there may be an association between the rs4238001-CC genotype (p=0.002), smoking (p=0.026), and MI+ CHD in the presence of other risk factors associated with CHD, whereas haplotype analysis confirmed that patients with MI+ CHD (rs5888-C, rs10846744-G, and rs4238001-C alleles) and CCC (rs5888-C, rs10846744-C, and rs4238001-C alleles) haplotypes were highly frequent (p<0.01 and p=0.027, respectively). CONCLUSION: These results indicated that SR-BI gene variants show different distribution in patients with MI+ CHD compared with that in MI- control subjects, and these variants may have effects in favor of dyslipidemia.

SEPTIN12 c.474 G > A polymorphism as a risk factor in teratozoospermic patients.

Teratozoospermia is a condition related to poor morphologically normal sperm count below the lower reference limit, which could hinder natural conception. Single nucleotide polymorphisms (SNPs) in the genes involved in sperm production and testicular function are proved to be risk factors, resulting in decreased sperm parameters and defects in sperm morphology. c.474 G > A polymorphism in the SEPTIN12 gene which is one of the testis-specific genes creates a novel splice variant and the resulting truncated protein was previously found to be more prevalent in infertile men. We aimed to investigate the association of SEPTIN12 c.474 G > A polymorphism with male infertility in teratozoospermia patients. Forty-eight teratozoospermic patients, diagnosed according to Kruger's criteria and 164 fertile controls who fathered at least 1 child within 3 years without assisted reproductive technologies were included into our prospective randomized controlled study. PCR-RFLP method was used for genotyping. Although no statistical difference was found between teratozoospermic patients and fertile controls in terms of genotype distributions, significance was identified between the genotypes of all and non-smoking teratozoopermic patients in terms of neck defects. SEPTIN12 c.474 G > A polymorphism was shown to be associated with sperm neck defects in teratozoospermic patients using the dominant statistical model. Smoking was identified as a risk factor for the sperm morphology defects in teratozoospermic A allele carriers.

The comparison of serum TGF-beta levels and associated polymorphisms in patients with coronary artery ectasia and normal coronary artery.

BACKGROUND: Coronary artery ectasia (CAE) is described as the enlargement of a coronary artery segment by 1.5 times or more, which is generally associated with the atherosclerotic process. Atherosclerotic changes lead to arterial remodeling result in CAE. In our study, we measured serum transforming growth factor (TGF)-ß1 levels, which have a protective role against atherosclerosis. Further, we aimed to assess the TGF-ß1 gene variants rs1800469 (-509C>T, c.-1347C>T) and rs1800470 (c.+29T>C, p.Pro10Leu, rs1982073), which might have an effect on TGF production. Overall, 2877 patients were screened including 56 patients with CAE and 44 patients with normal coronary arteries who were included in the study. Serum TGF-ß1 levels were measured using ELISA and compared between two groups. Additionally, TGF-ß1 rs1800469 and rs1800470 gene variations were determined using TaqMan® SNP Genotyping Assays. RESULTS: Serum TGF-ß1 levels were significantly lower in patients with CAE than in controls (p=0.012). However, there was no difference in terms of the genotype and allele distributions of TGF-ß1 rs1800469 and rs1800470 polymorphisms. Serum TGF-ß1 levels were higher in individuals carrying the TGF-ß1 rs1800470 G allele (GG+AG) than in individuals with normal homozygous AA genotype in the CAE group (p=0.012). CONCLUSION: Our findings suggest that lower serum TGF-ß1 levels are associated with an increased risk for CAE development and that TGF-ß1 polymorphisms exert a protective effect. Furthermore, TGF-ß1 rs1800470 G allele carriers were shown to have higher TGF-ß1 levels in the CAE group. This suggests that having the G allele in the TGF-ß1 rs1800470 polymorphism could prevent CAE development.

Interactive effects of interferon-gamma functional single nucleotid polymorphism (+874 T/A) with cardiovascular risk factors in coronary heart disease and early myocardial infarction risk.

Atherosclerosis is an inflammatory disease characterized by extensive lipid accumulation in the artery wall. Throughout the atherosclerotic process, interferon-gamma (IFN-γ), which is an important pro-inflammatory cytokine, plays a central role in atherosclerotic plaque instability and the occurrence of myocardial infarction (MI). In this study, we aimed to investigate the relationship between IFN-γ +874 T/A (rs2430561) polymorphism and coronary heart disease (CHD) as well as its effects on MI and CHD. Three hundred and ninety patients with CHD (229 with MI, 161 without MI) and 233 healthy controls were screened by the amplification refractory mutation system (ARMS) PCR method for IFN-γ +874 T/A polymorphism. For MI risk, early adult age was important risk factors and the risk was increased with IFN-γ +874 T/A polymorphism. IFN-γ T allele was significantly increased in the CHD patients with age≤45 (p = 0.048) and patients with history of MI (p = 0.007). As IFN-γ is an inflammatory cytokine with an emerging role in the atherosclerotic process, it was suggested that inhibition of IFN-γ activity could be a therapeutic strategy to stabilize human atherosclerotic plaque. Our findings support the association between MI risk and IFN-γ +874 T/A polymorphism in the Turkish population, particularly by increasing the level of IFN-γ in young patients, thereby causing rupture of vulnerable plaques in atherosclerotic lesions. Identification of the IFN-γ +874 T/A gene variants as risk factors for early CHD and MI development may be a practical biomarker to guide the MI risk process and determine the ideal therapeutic approach.

BMP1 5'UTR + 104 T/C gene variation: can be a predictive marker for serum HDL and apoprotein A1 levels in male patients with coronary heart disease.

Apolipoprotein A1 (Apo A1), the major protein of HDL, is secreted as a proprotein and then is cleaved by C-terminal procollagen endoproteinase/bone morphogenetic protein-1 (BMP1). BMP1 stimulates the conversion of newly secreted proapo A1 to its phospholipid-binding form. Therefore, genetic variations of BMP1 gene may affect serum ApoA1 and HDL levels. We aimed to investigate the effects of the functional 5'UTR + 104 (T/C) variant of BMP1 on serum ApoA1 and HDL levels and risk of coronary heart disease (CHD) in this study. The BMP1 5'UTR + 104 (T/C) (rs143383) variation was determined in 131 male patients with CHD and 51 male controls by real-time polymerase chain reaction technique. ApoA1 levels were measured by immunoturbidimetry. The serum Apo-A1 levels were found higher in controls with the BMP1-CC genotype than those with the T-allele (p < 0.001). Our findings show the association of this variation with serum ApoA1 and HDL-C levels which increase in the order of CT < TT < CC in the controls. No effect was found on ApoA1 and HDL-C levels in CHD patients, as it was observed in the controls. However, the BMP1-TT genotype was associated with higher triglyceride (TG) levels as compared to C-allele (p = 0.009). These discrepancies could be due to statin therapy which has dominant effects on lowering cholesterol levels comparing to TG levels. Our results indicated that the BMP1 5'UTR + 104 (T/C) variation may affect the serum ApoA1 and lipoprotein levels depending on statin therapy so that contributes to the development of CHD.

Effect of air bubbles localization and migration after embryo transfer on assisted reproductive technology outcome.

OBJECTIVE: To evaluate the effect of embryo flash position and movement of the air bubbles at 1 and 60 minutes after ET on clinical pregnancy rates (PRs). DESIGN: Prospective clinical trial. SETTING: University fertility clinic. PATIENT(S): A total of 230 fresh ultrasound-guided ETs performed by a single physician (C.F.) at the IVF center of Yeditepe University Hospital between September 2016 and February 2017 were included. INTERVENTION(S): Transabdominal ultrasonographic guidance at ET. MAIN OUTCOME MEASURE(S): Clinical PRs. RESULT(S): There was no significant difference in terms of clinical PRs between women with embryo flash located >15 mm and <15 mm from the fundus at 1 or 60 minutes (P=.6 and P=.7, respectively). The PRs in women with embryo flash located <15 mm and >15 mm from the fundus were 47% and 60%, respectively (P=.6). The clinical intrauterine PRs were 69.5%, 38.5%, and 19.1% in fundal, static, and cervical, respectively. The highest PR was in fundal when compared with others (P<.01). The clinical PR appears to be associated with the embryo flash movement/migration and the PR was dramatically reduced when the embryo migrated from its original position toward the cervix at 60 minutes. CONCLUSION(S): We concluded that clinical PR appears to be associated with the embryo flash movement/migration at 60 minutes after ET and embryo flash movement toward the fundus is associated with higher clinical PRs. Further well-designed randomized controlled trials are required to optimize ET technique in the future.