ANALYSIS OF CYTOCHROME P4501A1 GENETIC POLYMORPHISMS IN PATIENTS WITH ISCHEMIC STROKE Adali, Ayse &Ccedil / inar M.Sc., Department of Biochemistry Supervisor: Prof. Dr. Orhan Adali Co-Supervisor: Dr. Birsen Can Demird&ouml / gen January 2011, 179 pages Stroke is the third leading cause of death worldwide and results in serious disabilities. Cytochrome P450 1A1 gene (CYP1A1) is a highly polymorphic gene encoding its corresponding xenobiotic metabolizing enzyme which is responsible from the metabolism of carcinogenic polycyclic aromatic hydrocarbons (PAHs) that are engaged with the formation of free radicals. Atherosclerosis is a major cause of ischemic stroke and this pathology may be associated with the disruption of vascular homeostasis due to the formation of these chemicals. The main objective of this study was to investigate the coding region (A4889G) and non-coding region (T6235C) polymorphisms of the CYP1A1 gene as a risk factor for ischemic stroke. The study group in Turkish population consisted of 226 unrelated ischemic stroke patients and 113 control subjects. There was no statistically significant difference between the groups with respect to age and gender. Total blood samples were obtained from G&uuml / lhane Military Medical Academy Hospital, Neurology Department, Ankara. In stroke patients, hypertension, diabetes mellitus, smoking and obesity were at least 2 times more common and high density lipoprotein cholesterol (HDL-C) was significantly lower than controls. The frequency of mutant allele 4889G was 0.445 in patients and was nearly the same with controls. The frequency of mutant allele 6235C was 0.151 in patients and was significantly higher in controls (0.226, P=0.015). The risk of diabetic, smoker and obese individuals having ischemic stroke was significantly higher in 4889G allele carriers (AG+GG / Odds ratio / OR= 2.1, 2.4 and 3, respectively). The risk of hypertensive and diabetic individuals having ischemic stroke was higher in 6235TT genotypic people (OR= 3 and 2.2, respectively). On the contrary, the risk of smoker and obese individuals having ischemic stroke was significantly higher in 6235 C allele carriers (OR=5.3 and 3.7, respectively). Logistic regression analysis revealed that hypertension, smoking, levels of low density lipoprotein cholesterol (LDL-C) and HDL-C and 6235C allele were significant predictors of stroke. In this analysis, high level of LDL-C was found to be associated with almost 1.5-fold risk of ischemic stroke. On the other hand, HDL-C and having mutant 6235C allele decreased the risk of ischemic stroke 2.5 and 2-fold, respectively. This is the first study investigating the relation between A4889G polymorphism and stroke risk. Additionally, in Turkish population A4889G and T6235C polymorphisms were analyzed for the first time in terms of its relation to ischemic stroke. The present study demonstrated that the frequency of mutant 4889G allele was nearly the same in stroke patients and control subjects / whereas the frequency of mutant 6235 C allele was higher in control subjects than in stroke patients. Consequently, we decided that carrying mutant 4889 G allele does not constitute a risk for ischemic stroke and carrying mutant 6235C allele may have a protective effect against stroke.

Stroke is characterized with loss of one or more functions of the body resulted by inadequate blood supply to the brain. Most of the cases result from a blood clot forms on an atherosclerotic plaque in the brain which is called as ischemic stroke. Structure of the arteries and vascular tone are listed in major determinants in the development of the disorder. Soluble epoxide hydrolase (sEH, EPHX2) catalyzes conversion of epoxyeicosatrienoic acids to inactive diol metabolites. EETs are potent vasodilators that participate in the regulation of vascular tone and cerebral blood flow. Microsomal epoxide hydrolase (mEH, EPHX1) is a critical phase I enzyme that catalyzes the conversion of various xenobiotic epoxide substrates and polycyclic aromatic hydrocarbons (PAHs). Animal studies show that tobacco smoke mutagens such as PAHs and heterocyclic amines directly increase the development of atherosclerotic lesions. The main purpose of this study is evaluation of effect of Arg287Gln single nucleotide polymorphism of EPHX2 gene and Tyr113His and His139Arg single nucleotide polymorphisms of EPHX1 gene as a risk factor for ischemic stroke in Turkish population. Blood samples of 237 ischemic stroke patients and 120 controls were collected and all polymorphisms were determined by PCR-RFLP method. Mutant allele frequencies in terms of Arg287Gln polymorphism of EPHX2 gene (A) were found as 0.08 for patient group and 0.09 for controls. Tyr113His polymorphism of EPHX1 gene (C) were found as 0.27 for patient group and 0.31 for controls when, His139Arg polymorphism of EPHX1 gene (G) were 0.820 and 0.814 for patient and control groups, respectively. The differences between mutant allele frequencies of patients and controls were not found to be statistically significant. Subgroup analysis was used to investigate the effects of conventional vascular factors according to the genotypes in the stroke susceptibility. Smoking, diabetes, obesity and hypertension were found to significantly increase the risk of having stroke. More detailed analysis on these factors with respect to genotypes showed that the risk of hypertensive individuals having ischemic stroke was higher in wild type homozygous genotype groups of Tyr113His (TT) and His139Arg (AA) polymorphisms and heterozygous and mutant homozygous genotypes of Arg287Gln (GA+AA) polymorphism than their counterparts (OR= 3.21, 3.15 and 4.69, respectively). Smoker people within the heterozygous and mutant homozygous genotypes group of Arg287His (GA+AA) polymorphism and wild type homozygous group of His139Arg (AA) polymorphism were found to be more susceptible to have stroke (OR= 11.81 and 4.78 respectively). Finally, diabetes mellitus was found to double the risk of having stroke regardless of the genetic background. Logistic regression analyses were used to ascertain the effects of vascular factors, lipid parameters and genotypes in the stroke susceptibility. LDL-cholesterol (OR=1.46 / 95%CI, 1.12-1.89, P=0.00), smoking (OR=3.46 / 95%CI, 1.66-7.21, P=0.00) and hypertension (OR=3.19 / 95%CI, 1.92-5.30, P=0.00) were found to be significant risk factors for ischemic stroke, whereas HDL (OR=0.27 / 95%CI, 0.12-0.65, P=0.02) was found to be a protective factor in general population. In this study, the relation of Tyr113His and His139Arg polymorphisms of EPHX1 gene and risk of ischemic stroke is investigated for the first time in literature while, Arg287Gln polymorphism and ischemic stroke risk in Turkish population was studied for the first time.

Stroke is the third leading cause of death and the most common cause of disabilities worldwide. Apolipoprotein A5 gene (APO A5), which encodes a 369 amino acid protein called Apolipoprotein AV (apo AV), has several single nucleotide polymorphisms (SNPs) found to be associated with altered triglyceride (TG) levels. Atherosclerosis is a major cause of ischemic stroke and this pathology may be associated with variability of TG levels. The main objective of this study was to investigate the coding region (c.553G&gt / T) and promoter region (-1131T/C) polymorphisms of the APO A5 gene as a risk factor for ischemic stroke. The study group in Turkish population consisted of 198 unrelated ischemic stroke patients and 130 control subjects. There was no statistically significant difference between the groups with respect to age and gender. Total blood samples were obtained from G&uuml / lhane Military Medical Academy Hospital, Neurology Department, Ankara. In stroke patients, hypertension and diabetes were 2.5 times more common and high-density lipoprotein cholesterol (HDL-C) was significantly lower than controls. Logistic regression analysis showed that hypertension, diabetes and smoking were significant predictors of stroke. The frequency of risky alleles c.553T and -1131C were 0.003 and 0.098, respectively, in patients and were nearly the same with controls. The risk of hypertensive and diabetic individuals having ischemic stroke was higher in -1131C allele carriers (Odds ratio / OR= 3.4 and 6.4, respectively) than -1131TT individuals (OR= 2.3 and 1.9, respectively). Stroke patients with -1131C allele had significantly higher TG levels (1.70 mmol/L) and lower HDL-C levels (1.05 mmol/L) when compared to controls (1.35 mmol/L and 1.20 mmol/L, respectively) with the same genotype. Logistic regression analysis revealed elevated TG level to be associated with 2.2-fold and low levels of HDL-C to be associated with 1.8-fold increase in the risk of ischemic stroke versus control status. This is the first study investigating the relation between APO A5 c.553G&gt / T polymorphism and stroke risk. Additionally, in Turkish population -1131T/C polymorphism was analyzed for the first time in terms of its relation to ischemic stroke. The present study demonstrated that the frequency of risky alleles c.553T and-1131C were nearly the same in stroke patients and control subjects. Consequently, we decided that carrying minor alleles of c.553G&gt / T and-1131T/C polymorphisms do not constitute a risk for ischemic stroke.

Stroke, a major cause of death and disability, is described as interruption or severe reduction of blood flow in cerebral arteries. Oxidative stress plays an important role in the pathogenesis of atherosclerosis and carotid atherosclerosis is a risk factor for stroke. Combination of multiple environmental and genetic risk factors is thought to increase susceptibility to the development of this disease. Therefore, investigation of the polymorphisms of drug metabolizing enzymes is of crucial importance to determine the molecular etiology of the disease. The main objective of this study was to investigate the possible association between polymorphisms of enzymes causing oxidative stress (CYP2E1, FMO3 and NOS3) and enzymes protecting against oxidative stress (GST and NQO1), and the pathogenesis of atherosclerosis and ischemic stroke risk. The study population consisted of 245 unrelated ischemic stroke patients and 145 healthy control subjects. There was no statistically difference between the patient and control groups in terms of age and gender. Hypertension, diabetes, smoking and obesity were found to be at least 2 times more common in stroke patients than controls. While total cholesterol, triglyceride and LDL-cholesterol level were higher in stroke patients, HDL-cholesterol level was lower in stroke patients when compared to controls. In the case-control analyses for the risk of ischemic stroke, CYP2E1*5B mutant allele, *5B was found to be associated with the development of disease (Odds Ratio / OR=7.876, 95%CI=1.025-60.525, P=0.019). In addition, significant difference was observed between stroke patients and controls with respect to CYP2E1*5B genotype distribution (OR=0.869, 95%CI=1.044-62.339, P=0.017). On the other hand, in the NQO1*2 polymorphism, together with NQO1 heterozygote (*1*2), NQO1 homozygote mutant (*2*2) genotype was found protective against ischemic stroke (OR=0.627, 95%CI=0.414-0.950, P=0.027). The risk of hypertensive individuals having stroke was highest in the FMO3 472GA group (OR=6.110, P=0.000). In diabetics, GSTP1 313AG genotype was found to be the highest risk factor for stroke (OR=3.808 P=0.001). On the other hand, NQO1 *1*2 heterozygote genotype was associated with 5 times increased risk for stroke in smokers (OR=5.000, P=0.000). In addition GSTM1 present genotype constituted 8 times increased stroke risk in obese individuals (OR=8.068, P=0.001). Logistic regression analysis revealed that hypertension, diabetes mellitus, obesity and smoking were significant risk factors for stroke. On the other hand, HDL-cholesterol and having NQO1 *1*2 heterozygote genotype were found to be protective factors against stroke.

ABSTRACT THE ECONOMIC IMPACT OF THE 1923 GRECO-TURKISH POPULATION EXCHANGE UPON TURKEY Alpan, Aytek Soner M. Sc., Department of Economics Supervisor: Assoc. Prof. Dr. Onur Yildirim August 2008, 167 pages The Convention Concerning the Exchange of Greek and Turkish Populations signed on January 30, 1923 at Lausanne resulted in the first compulsory population exchange under the auspices of an international organization, namely the League of Nations. The Greco-Turkish Population Exchange marked a turning point for Greece and Turkey with regard to its demographic, social, political and economic effects. Although the multifaceted effects of the Exchange upon Greece have been extensively studied by the scholars of different disciplines, the Turkish scholarship is very limited in terms of documenting and analyzing the role of this event in the history of modern Turkey. The present study aims to fill this gap by assessing the economic effects of this event upon Turkey. This thesis fulfils the above task by examining the transformation of the basic sectors in the Turkish economy during the post-Exchange period. We argue that the Population Exchange had significant effects upon the Turkish economy. For example, in the agricultural sector the capitalist property relations on land were reinforced and the production patterns in certain agricultural crops were subject to a considerable degree of change. As far as the industry is concerned, the production of certain commodities deteriorated due to the rising competition between Turkey and Greece over the manufactured goods. The worsening international economic conditions exacerbated the effects of this competition upon the Turkish economy. Lastly, with the transfer of the Anatolian Greek merchants to Greece, Anatolia&rsquo / s commercial links with foreign markets weakened much to the detriment of the Turkish economy. The intermediary position of the Greek merchants was gradually substituted by the newly-emerging Turkish mercantile bourgeoisie after the Exchange. This thesis consists of five chapters. Chapter 1 introduces the subject and provides a survey of the related literature. Chapter 2 examines the effects of the Exchange upon agriculture and land tenure system. Chapter 3 is designed to evaluate the transformation of the industrial base inherited from the Ottoman Empire by certain factors including the Exchange. Chapter 4 deals with the effects of the transfer of the Anatolian Greeks and the arrival of the refugees upon the commerce. Chapter 5 presents general and specific conclusions in the light of previous chapters.

Acute lymphoblastic leukemia (ALL) is the most common type of cancer affecting children in the world and in our country. The exact molecular etiology of the disease still remains to be elucidated. This study hypothesized that four genes, namely CYP2E1*5B, *6, and *7B, NQO1*2 SNPs, GSTM1 null and GSTT1 null, alone or in combination, could contribute to the risk of development of childhood ALL. Also interactions of these polymorphisms with non-genetic risk factors were investigated. The genotyping of these polymorphisms were done on 209 healthy subjects, and 185 patients with childhood ALL, in Turkish population. Venous blood samples were collected and genomic DNA was isolated from these samples. Genotyping was done by PCR-RFLP techniques. In the case-control analyses for the risk of development of childhood ALL, only GSTT1 null was found to be associated with the development of disease (OR= 1.8, p=0.01). CYP2E1*5B and *6 combination showed an increased risk of 2.7 fold (p= 0.04). Also co-presence of CYP2E1*6-GSTT1 and CYP2E1*7B-GSTT1 polymorphisms increased the risk significantly above 4.0 fold. The risk increased more to 7.6 fold, when CYP2E1*5B,*6 and GSTT1 null were considered together, with borderline significance (p=0.04). When interaction of exposure to cigarette smoke and genetic polymorphisms were investigated, NQO1*2 and GSTM1 null were turned out to be significant risk factors for the development of disease when the parental or child&rsquo / s postnatal exposure to cigarette smoke was considered. This study presented several new findings to the literature in terms of genetic epidemiology of childhood ALL. The present work would also contribute to public health in determining the susceptibility of the Turkish population to childhood ALL.

Cytochrome P4502E1 (CYP2E1), the ethanol-inducible isoform of cytochrome P450 superfamily, catalyzes many low molecular weight endogenous and exogenous compounds, including ethanol, acetone, drugs like acetaminophen and chlorzoxazone, and industrial solvents like benzene and styrene, most of which are carcinogenic. Besides, it has a high capacity to produce reactive oxygen species. CYP2E1 is induced by ethanol and isoniazid, as well by some pathophysiological conditions like diabetes and starvation. CYP2E1 gene shows genetic polymorphisms which are thought to play a major role in interindividual variability in drug response and in susceptibility to chemical-induced diseases, like several types of cancers. It is well established that CYP2E1 polymorphisms vary markedly in frequency among different ethnic and racial groups. Therefore, in this study, the frequency of two important CYP2E1 polymorphisms / the single nucleotide polymorphisms C-1019T / G-1259C in 5&rsquo / -flanking region and T7678A poymorphism in intron 6, in Turkish population was investigated. For this purpose, whole blood samples were collected from 132 healthy volunteers representing Turkish population and genomic DNA for each subject was isolated in intact form. The genotypes were determined by PCR amplification of corresponding regions followed by restriction endonuclease RsaI, PstI (for C-1019T / G-1259C SNPs) and DraI (for T7678A SNP) digestions. The genotype frequencies, for C-1019T / G-1259C SNPs, which are in complete linkage disequilibrium, were investigated on 116 DNA samples, and determined as 97.4% for homozygous wild type (c1/c1), 2.6% for heterozygotes (c1/c2) and 0.0% for homozygous mutants (c2c2). The allele frequency of wild type allele (c1) was calculated as 98.7% and that of mutated allele (c2) as 1.3%. The genotype frequencies for T7678A SNP, investigated in 108 DNA samples were determined as 80.6% for homozygous wild type (DD), 19.4% for heterozygotes (CD) and 0.0% for homozygous mutants (CC). The corresponding allele frequencies were 90.3% for wild type allele (D), and 9.7% for mutated allele (C). Genotype frequencies of both polymorphisms fit Hardy-Weinberg equation and showed no significant difference with respect to gender. The genotype distributions of both polymorphisms showed similarity when compared to other Caucasian populations like French, Swedish, German, and Italian populations, while both polymorphisms studied differed significantly from Chilean, Japanese, Taiwanese and Chinese populations, as compared with Chi-Square test.