Hulya Yilmaz

Oxidative DNA base damage and antioxidant enzyme levels in childhood acute lymphoblastic leukemia

We have investigated the levels of several antioxidant enzymes and the level of oxidative DNA base damage in lymphocytes of children with acute lymphoblastic leukemia (ALL) and in disease‐free children. Children with ALL had just been diagnosed with the disease and had received no therapy prior to obtaining blood samples. A multitude of typical hydroxyl radical‐induced base lesions in lymphocyte DNA of children were identified and quantified by gas chromatography‐isotope dilution mass spectrometry. Higher levels of DNA base lesions were observed in patients with ALL than in children without the disease. The levels of the antioxidant enzymes glutathione peroxidase, catalase and superoxide dismutase in lymphocytes of ALL patients were lower than in lymphocytes of controls. These findings are in agreement with earlier observations in various types of adulthood cancer. Some of the identified DNA base lesions are known to possess premutagenic properties and may play a role in carcinogenesis. The results may indicate a possible link between decreased activities of antioxidant enzymes and increased levels of DNA base lesions due to oxidative damage, and support the notion that free radical reactions may be increased in malignant cells.

Angiotensin converting enzyme I/D, angiotensinogen T174M-M235T and angiotensin II type 1 receptor A1166C gene polymorphisms in Turkish hypertensive patients

Essential hypertension is a multifactorial disease in which genetic and enviromental factors play an important role. These factors differ in each population. As there are no existing data for the Turkish population, we investigated four Renin Angiotensin System (RAS) gene polymorphisms, the angiotensin converting enzyme (ACE), angiotensinogen (AGN) M235T/T174M and angiotensin II type 1 receptor A1166C polymorphism in 109 hypertensive and 86 normotensive Turkish subjects. Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP), and agarose gel electrophoresis tecniques were used to determine these polymorphism. The frequencies of person that carry ACE D allel (DD+ID) was significantly higher in hypertensive group (99.1%) than controls (80%) (P<0.000). M235T TT genotype was also found significantly higher in hypertensives than control group (20% vs 2.7%; P<0.001). The frequency of AGN 174M allele was higher in the hypertensive group than control subjects (8.76% vs 4.81%). Frequency of ATR1 C allele (AC+CC genotypes) was found higher hypertensives than controls (39.4% vs 25.9%; P = 0.054). Our results suggest that an interaction exists between the RAS genes and hypertension in Turkish population.

Association between manganese superoxide dismutase polymorphism and risk of lung cancer

Manganese superoxide dismutase (MnSOD) is one of the major enzymes responsible for the defense against oxidative damage due to reactive oxygen species (ROS) in the mitochondria. C-->T substitution in the MnSOD gene (SOD2) produces an Ala-->Val change at amino acid 16, in the mitochondrial targeting sequence of the MnSOD precursor. This seems to reduce transport of the enzyme into mitochondria, decreasing its defense capacity against oxidative stress. The present case-control study was conducted to investigate the association of SOD2 genetic polymorphism with individual susceptibility to lung cancer. Ala16Val polymorphisms were determined using polymerase chain reaction, restriction fragment length polymorphism mapping, and agarose gel electrophoresis techniques in 100 lung cancer patients and 50 healthy control subjects. The frequency of the Val allele (OR=1.297, 95% CI=1.095-1.536) and the Val/Val genotype (OR=7.00, 95% CI=2.282-21.476) was significantly higher in lung cancer patients than in control subjects. There was a combined effect of Val/Val genotype as a genetic factor with smoking as an environment factor (OR=2.24). The increase in risk of lung cancer was lesser with this combined effect than with the Val/Val genotype alone. Thus, the Val/Val genotype of SOD2 may be associated with lung cancer in a Turkish population.

Genetic Polymorphisms Contribute to Acute Kidney Injury after Coronary Artery Bypass Grafting

BACKGROUND Acute kidney injury is one of the most serious complications after cardiac surgery. Genetic polymorphisms are reported to be associated with postoperative renal impairment. The aim of this study was to investigate the relationship between selected gene polymorphisms and acute kidney injury after cardiac surgery. METHODS Two hundred forty-eight elective coronary artery bypass grafting procedure patients were enrolled in the study. Angiotensin-converting enzyme (ACE) II, ID, and DD, apolipoprotein E (APO E), and angiotensin II type 1 receptor (AGTR1) A1166C genotypes were detected by polymerase chain reaction. Plasma levels of ACE were analyzed by enzyme-linked immunosorbent assay. Acute kidney injury after cardiac surgery was graded according to the RIFLE (risk, injury, failure, loss, and end-stage kidney disease) classification. RESULTS In our study, 21.8% of patients had acute renal impairment after cardiac surgery. Among the 54 patients with acute kidney injury, ACE D allele frequency was 0.620. The plasma levels of ACE were significantly higher in the D allele carriers (P = .018). Three of the 54 patients with acute kidney injury were APO E epsilon 4 allele carriers (P = .002). AGTR1 C allele carriers constituted 46% of all patients with postoperative acute kidney injury. There was no statistically significant difference between A allele homozygotes and C allele carriers with respect to postoperative renal dysfunction (P > .05). CONCLUSIONS The present findings support the hypothesis that ACE I/D and APO E gene polymorphisms may play a role in the development of acute kidney injury after cardiac surgery. However, AGTR1 does not have a unique association with postoperative renal impairment.

Apolopoprotein-E gene polymorphism and lipid profiles in Alzheimer's disease

In this study, the relationship between lipid profiles of sera and apolipoprotein E (apo E) gene polymorphism was investigated in 35 patients with Alzheimers disease (AD) and 29 healthy people. Apo E genotypes and allele frequencies of the AD patient group were: apo E2/3, 2 (5.7 percent); apo E2/4, 1 (2.9 percent); apo E3/3, 26 (74.3 percent); apo E3/4, 5 (14.3 percent); apo E4/4, 1 (2.9 percent); 2, 3(4.2 percent); 3, 59 (84.2 percent); 4, 8 (11.4 percent). The healthy groups apo E genotypes and allele frequencies were: apo E2/3, 1 (3.4 percent); apo E3/3, 27 (93.1 percent); apo E3/4, 1 (3.4 percent); 2, 1 (1.7 percent); 3, 56 (96.5 percent); 4, 1 (1.7 percent). In Alzheimers cases, 4 allele frequencies increased significantly as compared to the healthy group (p < 0.05). When the effects of the apo E isoforms on lipid profiles were evaluated, a relationship between apo E 4 allele and high total levels of serum cholesterol was found, whereas of apo E 2 allele was associated with the low total cholesterol of serum, although the difference was not statistically significant (p > 0.05). This study confirms the association of apo E 4 allele with lipid profiles in AD patients.

Association Between Angiotensin-Converting Enzyme Gene Polymorphism and Coronary Artery Disease

An insertion/deletion (I/D) polymorphism in the gene for angiotensin‐converting enzyme (ACE) is associated with myocardial infarction and other cardiac pathology. There is evidence for a role of the renin‐angiotensin system in cell growth and in the repair of damaged arterial walls, so the ACE gene is postulated to be a candidate gene affecting the important clinical problem of coronary artery disease (CAD). In view of the clinical importance of the ACE as a major marker of cardiovascular diseases, we investigated the I/D polymorphism of the ACE gene in Turkish CAD patients in comparison with control subjects to evaluate a possible association between CAD and the gene encoding ACE. Polymerase chain reaction, restriction fragment length polymorphism, and agarose gel electrophoresis techniques were used to determine the ACE genotype in 58 subjects. The frequencies of ACE D and ACE I allele among the patients with CAD were 62.26% and 37.73% and in the control subjects were 49.3% and 50.76%, respectively. The greater frequency of deletion allele (D) was in the CAD group than in the control subjects was significant (P < 0.01).

Association of pre-eclampsia with hyperhomocysteinaemia and methylenetetrahydrofolate reductase gene C677T polymorphism in a Turkish population.

Background:  Hyperhomocysteinaemia is a common finding in a wide variety of pathological conditions that exhibit endothelial disturbances. In the pathogenesis of pre‐eclampsia, endothelial cell activation or dysfunction has been proposed as a central feature, and the presence of hyperhomocysteinaemia in varying degrees has been detected. One of the known causes of hyperhomocysteinaemia is polymorphism in the methylenetetrahydrofolate reductase gene that lowers the activity of the enzyme.

Increased plasma levels of interleukin-6 and interleukin-8 in β -thalassaemia major

Several immunological defects can be found in patients with beta-thalassaemia, among which the impairment of neurophil and macrophage phagocytic and killing functions and the production of some cytokines are the most important. It is known that interleukin-6 (IL-6) and interleukin-8 (IL-8) are important components of the pro-inflammatory response. The plasma levels of these cytokines may be relevant in the pathophysiology of beta-thalassaemia. To assess this hypothesis, the plasma IL-6 and IL-8 concentrations in patients with beta-thalassaemia, were investigated. Fourteen patients with thalassaemia major were studied by evaluating body iron status, iron supply for erythropoiesis, and plasma IL-6 and IL-8 levels, together with 12 age-matched healthy controls. The plasma levels of IL-6 and IL-8 were determined by enzyme-linked immunosorbent assay (ELISA). Patients with beta-thalassaemia were found to have higher IL-8 concentrations than normal controls (p < 0.001) and plasma IL-6 concentrations increased significantly in the beta-thalassaemic patients compared with control subjects (p = 0.01). Serum ferritin levels of beta-thalassaemic patients were significantly higher than those of control groups (p < 0.05). IL-8 levels correlated with ferritin levels (r = 0.694; p < 0.05) and the total number of transfusions (r = 0.64; p < 0.05). Plasma IL-6 levels in beta-thalassaemic patients did not correlate with any clinical, haematological or biochemical parameters. It was also found that plasma IL-8 levels in the patients who had blood transfusions over 100 times were significantly higher than those of under 100 times (p < 0.05), whereas there was no statistical difference for IL-6. Markedly increased plasma IL-6 and IL-8 levels were documented in patients with beta-thalassaemia. Increased production of IL-6 and IL-8 might have contributed to abnormalities in iron metabolism and it is probably due to overstimulation of macrophages. Before a clinical value can be ascribed to these changes in plasma cytokine levels in beta-thalassaemia, the follow-up samples of larger series of patients with 8-thalassaemia should be evaluated.

Interaction between apolipoprotein-E and angiotensin-converting enzyme genotype in Alzheimer's disease

Both apolipoprotein-E (apo-E) 4 allele and angiotensinconverting enzyme (ACE) deletion (D) polymorphism have been associated with a high risk for coronary heart disease. Increased frequency of the 4 allele has also been reported in patients with late-onset of familial and sporadic Alzheimers disease (AD). The primary aim of this study is to examine the possible relationship between the ACE gene polymorphism and AD. The second aim of this study is to explore the relation of the ACE and apo-E genotypes with AD. Polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), and agarose gel electrophoresis techniques were used to determine the apo-E and ACE genotypes. The frequencies of ACE D and ACE insertion (I) allele among AD patients and controls were 55.7 percent versus 44.2 percent and 51.7 versus 48.2 percent, respectively. Apo-E allele frequencies in the AD group for 2, 3 and 4 were, 1.7 percent, 96.5 percent, and 1.7 percent, respectively. The apo-E allele frequencies of healthy groups for 2, 3 and 4 were 1 percent, 56 percent, and 1.7 percent, respectively. In conclusion ACE D and apo 4 allele were found to be more frequent in patients with Alzheimers disease than in the control group.

Manganese superoxide dismutase gene polymorphism, MnSOD plasma levels and risk of epithelial ovarian cancer

Aim:  We aimed to confirm any relation between the manganese‐containing superoxide dismutase (MnSOD) polymorphism and risk of ovarian carcinoma as well as to demonstrate any relation between the MnSOD mitochondrial signal sequence polymorphism and plasma MnSOD enzyme levels in women with ovarian carcinoma and healthy subjects.