Hatice Yildirim

Glutathione-S-transferase gene polymorphisms (GSTT1, GSTM1, GSTP1) as increased risk factors for asthma.

Objectives:  Asthma is a complex multifactorial disease with an obvious genetic predisposition, immunological aberration, and involvement of noxious environmental factors. Polymorphisms of the glutathione‐S‐transferase (GST) genes are known risk factors for some environmentally‐related diseases. In the present study, the hypothesis that polymorphisms in the GSTT1, GSTM1 and GSTP1 genes are associated with atopic and nonatopic asthma was examined.

N-Acetyltransferase 2 Gene Polymorphism and Presbycusis

Objectives/Hypothesis: The enzyme of N‐acetyltransferase (NAT) is involved in the metabolism and detoxification of cytotoxic and carcinogenic compounds as well as reactive oxygen species (ROS). The excessive amount of ROS generation occurs in the ageing inner ear. The exact etiopathogenesis of presbycusis is not known, but it is generally accepted that it is the result of series of insults, such as physiologic age‐related degeneration, noise exposure, medical disorders and their treatment, as well as hereditary susceptibility. The effect of aging shows a wide interindividual range; we aimed to investigate whether profiles of NAT2 genotypes may be associated with the risk of presbycusis.

Glutathione S-transferase gene polymorphism as a susceptibility factor in smoking-related coronary artery disease

Abstract.Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the world, and cigarette smoking is a major contributing factor to the disease. Glutathione S-transferase (GST) enzyme is implicated in the detoxification of carcinogens present in tobacco smoke and consequent polymorphisms in this gene may confer susceptibility to cardiovascular disease if DNA damage is important in CAD. Therefore, we examined this question in a case-control study of subjects having coronary atheroma by angiography and with a past history of myocardial infarction (MI). The study population consists of 247 healthy controls and 148 consecutive patients who had undergone coronary angiography for suspicion of coronary artery disease. DNA was extracted from whole blood, and the GSTM1 and GSTT1 polymorphisms were determined using a real-time polymerase chain reaction (PCR). We found that the null GSTM1 and GSTT1 genotypes were associated with an increase in the risk of developing coronary heart disease (OR = 1.14; 95% CI: 0.71 – 1.82; OR = 1.38; 95% CI: 0.82 – 2.32), respectively, but this increase was not significant. Patients who smoke having the null genotypes of GSTM1 (OR: 1.63 (1.10 – 2.63)) and GSTT1 (2.66 (1.50 – 4.72)) and both (3.20 (1.37 – 7.45)) were at a higher risk for developing coronary heart disease. In conclusion, the finding of a significant association between GSTM1 and T1 with smoking status may influence cardiovascular disease via DNA damage.

GSTM1 and GSTT1 null genotypes as possible heritable factors of rosacea

Purpose: Rosacea might be related to an increased activity of reactive oxygen species (ROS) and deficient function of the antioxidant system. Glutathione S‐transferases (GSTs) play a primer role in cellular defense against electrophilic chemical species and radical oxygen species. We hypothesized that increased ROS activity or decreased antioxidant potential, possibly induced by GST gene polymorphism, might have a pathogenic role in rosacea.

N-Acetyltransferase 2 Phenotype May Be Associated with Susceptibility to Age-Related Cataract

Free radicals and oxidative damage play roles in aging and age-related ocular diseases such as cataracts, so defensive mechanisms become important factors for protection. Because N-acetylation is involved in a wide variety of detoxification processes, this study was conducted to examine the relationship between the acetylator phenotypes and genotypes in a group of patients with age-related cataract. Sixty-one cases of age-related cataract and 104 controls were included in this study. Blood was collected in EDTA-containing tubes, and genomic DNA was extracted from the white blood cells by high pure PCR template preparation kit. Genotyping of NAT2 polymorphisms were detected by using a LightCycler-NAT2 mutation detection kit in real-time PCR. There was a significant difference in the distribution of the NAT2*6A acetylator phenotype between cases and the controls. The odds ratio of cataract for the NAT2*6A slow phenotype was 3.8 (95% CI = 1.08 to 13.11, p = 0.032) compared with the fast type. Our results suggest that slow acetylators are at higher risk of developing age-related cataracts than fast acetylators. As NAT2 is an important xenobiotic-metabolizing enzyme and theoretically xenobiotics such as ultraviolet B radiation, smoking, and alcohol use may induce cataract formation, NAT2 gene polymorphisms may be associated with genetic susceptibility of cataract.

Is GST Gene Polymorphism a Risk Factor in Developing Exfoliation Syndrome

Purpose: To evaluate the distribution of GSTM1, GSTP1, and GSTT1 gene polymorphisms in exfoliation syndrome (XFS) and the possible associations between the presence of exfoliation syndrome and glutathione S-transferase (GST) gene polymorphisms. Methods: Using a real-time polymerase chain reaction, GSTM1, GSTP1, and GSTT1 gene polymorphisms were detected in 60 patients with exfoliation syndrome, among which 71.7% had exfoliative glaucoma (43 patients), 16.7% had XFS with elevated intraocular pressure (IOP) (10 patients), and 11.7% had XFS only (7 cases), and in 65 otherwise healthy control group of similar age. Results: Although the exfoliation syndrome group presented a higher prevalence of the GSTM1 null and GSTP1 Ile/Val genotypes than the control group, this increase was not statistically significant. GSTT1 null and GSTP1 Val/Val polymorphisms were also not different among groups. The risk of exfoliation syndrome was not increased as the number of putative high-risk genotypes increase (p = 0.73). Conclusions: GSTM1, GSTP1, and GSTT1 gene polymorphisms were not different among exfoliation syndrome patients, with or without glaucoma, and the controls therefore GSTM1, GSTP1, and GSTT1 gene polymorphisms did not seem to be associated with the risk of development of exfoliation syndrome.

N‐acetyltransferase 2 polymorphisms in patients with Behcet's disease

It is possible that dietary, environmental factors and/or genetic polymorphisms in xenobiotic‐metabolizing enzymes may contribute to the development of Behcets disease. As N‐acetyltransferase (NAT) 2 is an important xenobiotic‐metabolizing enzyme and theoretically the nonacetylated xenobiotics may induce an autoimmune mechanism, the aim of the present study was to investigate whether the genetic polymorphism of NAT2 plays a role in susceptibility to Behcets disease. Forty Behcets disease patients and 82 control subjects were enrolled in the study. NAT2*5A, NAT2*6A, NAT27*A/B and NAT2*14A polymorphisms were detected by using real time PCR with LightCycler (Roche Diagnostics GmbH, Mannheim, Germany). The NAT2*5A and NAT2*6A mutant genotypes carried an increased risk of developing Behcets disease [odds ratio (OR) = 66.29, 95% confidence interval (CI) = 8.21–535.33; and OR = 24; 95% CI = 2.04–304.98, respectively]. The NAT2*7A/B and NAT2*14A gene polymorphisms were not an increased risk for developing Behcets disease. As a result of this study we conclude the NAT2 slow acetylator status may be a determinant in susceptibility to Behcets disease. This finding may have implications for the theories of the pathogenesis of the disease as well as for therapeutic aspects.

Cytochrome P450 polymorphisms in patients with Behcet's disease

Objectives  Although the etiopathogenesis of Behcets disease (BD) remains unknown, increased neutrophil functions such as chemotaxis, phagocytosis and excessive production of reactive oxygen species, including superoxide anion, may be responsible for the oxidative tissue damage observed in BD. Cytochrome P‐450 are a multigene family of enzymes involved in the detoxification and occasional activation of a wide variety of chemicals. Our aim was to investigate CYP2C9 and CYP2C19 polymorphisms in patients with BD.

Glutathione S-transferase GSTM 1, null genotype may be associated with susceptibility to age-related cataract.

BACKGROUND Age-related cataract (ARC) is the leading cause of visual disability and reversible blindness all over the world. The different expressions of GST isozymes among animals may explain the variations in the cataract formation caused by oxidative stress. OBJECTIVES In this study, we evaluated the distribution of GST gene polymorphisms in ARC patients and the possible associations between the presence of ARC and GST gene polymorphisms. MATERIAL AND METHODS The epidemiological data was collected by a standard questionnaire and blood samples were obtained from 130 ARC patients and 159 healthy controls. Data about smoking habits of the groups was recorded. Real-time polymerase chain reaction-based methods were used to detect genetic polymorphisms. RESULTS The GSTM 1 null genotype was found to carry an increased risk for developing ARC (OR: 1.84, 95% CI: 1.13-2.99). The frequency of the GSTT 1 null genotype was not significantly different among the ARC patients and the controls (OR: 1.0, 95% CI: 0.64-1.6). The GSTP 1 Val/Val genotype was also not significantly different among the ARC patients and control groups (OR: 1.06, 95% CI: 0.50-2.23). GSTM 1 null genotype was highly frequent in non-smokers (OR: 3.25, 95% CI: 1.66-6.35) and moderately frequent in smokers (OR: 2.50, 95% CI: 1.28-4.86). Also, carrying the combined genotypes of GSTM 1 null, GSTT 1 and GSTP 1 105-Val allele was seen to have an increased risk of developing ARC (OR: 2.91, 95% CI: 1.31-6.44). CONCLUSIONS This data may provide evidence that GSTM 1 gene polymorphisms may be associated with genetic susceptibility to develop ARC. Larger studies are warranted to verify these findings.

Increased Production of Nitric Oxide Mediates Selective Organ-Specific Effects of Endotoxin on Oxidative Stress

Endotoxemic shock is a systemic inflammatory response that is associated with increased nitric oxide (NO) production by inducible NO synthase (iNOS) which contributes to hypotension, vascular hyporeactivity, and multiple organ failure. Oxidative stress (OS) is a major contributing factor to high morbidity and mortality in endotoxemic shock. We have previously demonstrated that endotoxin-induced fall in blood pressure is associated with an increase in nitrite levels in serum, kidney, heart, thoracic aorta (TA), and superior mesenteric artery (SMA), a decrease in malondialdehyde (MDA) levels in the kidney, heart, TA, and SMA, and an increase in myeloperoxidase (MPO) activity in the heart and TA, but a decrease in the kidney and SMA of rats. In this study, we further investigated whether increased production of iNOS-derived NO contributes to endotoxin induced changes in the biomarkers of OS in the liver, lungs, brain, spleen, and femoral artery (FA) of rats. Endotoxin-induced increase in nitrite production was associated with a decrease in reduced glutathione levels in the liver, lungs, brain, spleen, and FA. MPO activity was increased by endotoxin in the lungs, spleen, and FA, but decreased in the liver and brain. MDA levels were increased by endotoxin in the lungs, brain, spleen, and FA, but were decreased in the liver. Activities of superoxide dismutase and catalase were decreased in the liver and spleen, but were increased in the lungs, brain, and FA. These effects of endotoxin were prevented by a selective iNOS inhibitor, phenylene-1,3-bis[ethane-2-isothiourea] dihydrobromide. These data suggest that iNOS-derived NO mediates selective organ-specific effects of endotoxin on OS.