Pharmacogenetics is the study of variability in drug response attributed to genetic variation. Olanzapine (OLA) is a widely used antipsychotic drug for schizophrenia treatment. The pharmacokinetics of OLA display large inter-individual variation leading to multiple-fold differences in drug exposure between patients at a given dose. This variation in turn gives rise to the need of individualized dosing in order to avoid concentration-dependent adverse effects and therapeutic failure. The observed variability has been partially explained by environmental and physiological factors. Genetically determined differences in drug metabolism represent a less studied source of variability. Precluded contribution by cytochrome P450 (CYP) 2D6 calls for evaluation of the other major OLA metabolizing enzymes. The objective of this thesis was to study pharmacogenetic influence of flavin-containing monooxygenase (FMO) 1 and 3, CYP1A2 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4 on therapeutic OLA exposure. We conducted genetic association studies applying gene re-sequencing and genotyping of candidate and tagging SNPs. Patients carrying the FMO1*6 allele displayed increased dose-adjusted concentrations (C/Ds) of OLA, in serum as well as cerebrospinal fluid. Patients who were homozygous for the FMO3 K158-G308 compound variant showed reduced C/Ds of OLA N-oxide metabolite, but no alteration in OLA exposure. This compound variant is expected to have clinical relevance primarily for non-African populations, since low frequencies were detected among native Africans. Deviation in OLA exposure was observed in carrier of a rare FMO3 mutation, predicted in silico to affect gene splicing. Reduced OLA exposure was observed in UGT1A4*3 carriers. The CYP1A2 -163(A) (CYP1A2*1F) variant was not associated with increase in CYP1A2-catalyzed OLA metabolism or reduction in OLA exposure. Correlations were detected for two cis-acting variants within the inter-genetic region of the CYP1A cluster and a trans-acting variant located upstream the locus encoding aryl hydrocarbon receptor. The inconsistent data reported for CYP1A2*1F could be explained by presence of ethnic specific haplotype structures incorporating the -163(A) variant. A continuously improved understanding of the wide range of factors that can influence pharmacokinetics and pharmacodynamics will increase the likelihood of achieving optimal treatment response for individual patients.

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.