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The disruption of the circadian system in bipolar disorder and its association with the polymorphism of L-type calcium channel
Filipovská, Eva ; Bendová, Zdeňka (advisor) ; Novosadová, Zuzana (referee)
Bipolar affective disorder is a serious psychiatric disease with prevalence of about 1% in general population. Typical symptoms are mood changes: manic periods are followed by depressions, with possible asymptomatic period of variable duration between them. It alters patient's everyday life and often leads to suicidal tendencies. Bipolar disorder is related to impaired circadian rhytms that are regulated from suprachiasmatic nuclei in hypothalamus. Impaired circadian rhytms in bipolar disorder are manifested by abnormalities of sleep and daily activity and by disrupted circadian secretion of several hormons. One of many factors that link bipolar disorder to circadian system at molecular level is the function of voltage-dependent calcium channels of L-type. Expression of these channels is regulated by the clock genes and their proper function is important for maintaining endogenous oscillations in the main oscillator located in suprachiasmatic nuclei. A common finding in patients with bipolar disorder is polymorphism of the gene for 1 subunit of the Cav1.2 channel. Abnormal function of calcium channels, consequent to the polymorphism, may be one of the causes that alter circadian rhytms in bipolar disorder. Key words: circadian system, suprachiasmatic nucleus, bipolar disorder, L-type calcium...
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Association of genetic polymorphism of oxidative stress with diabetes mellitus type 1 and 2
Kloboučková, Lucie ; Kotrbová - Kozak, Anna Katarzyna (advisor) ; Daňková, Pavlína (referee)
Diabetes mellitus is a chronic autoimmune disease in which the immune system attacks the insulin-secreting ß-cells in the pancreas. It leads to an absolute deficiency of insulin. Chronic hyperglycemia induces increased production of reactive oxygen species, which leads to a decrease of natural antioxidant level in blood, and it contributes to genesis of diabetes complications (e.g. vascular or pulmonic). Moreover, the oxidative stress results in onset of pancreas inflammations and the damage of its ß-cells. Aims: Our aim was to assess whether or not certain genotypes or their combinations occur with higher frequency among groups of patients of type 1 diabetes (T1D) and type 2 diabetes and in a control group of healthy individuals. Methods: The study included groups of 40 T1D patients, 40 T2D patients and 45 healthy individuals. The polymorphisms of genes involved in the oxidative stress response were analyzedby using RFLP, PCR with TaqMan probes and allele specific PCR. The target genes involved superoxide dismutase SOD1 and SOD3 genes; glutathione-S-transferase GSTM1, GSTT1, GSTP1 genes; glutathioneperoxidase gene GPX1 and catalase gene CAT. The levels of plasma malondialdehyde were measured by using liquid chromatography. Results: Statistically significant differences were found in the...
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Role of the FTO gene in the genetic determination of common multifactorial diseases
Dlouhá, Dana
Obesity is a risk factor for development of cardiovascular disease, diabetes type 2 and some cancers. Newly detected genetic risk factor for body weight is the FTO gene ("fat mass and obesity associated"). The aim of this thesis was determine 1) whether the presence of risk alleles correlate with BMI in Czech population and to determine 2) whether there is an association between variants in the FTO gene and risk of myocardial infarction/ acute coronary syndrome (MI/ ACS), 3) renal failure (ESRD), or 4) incidence of colorectal cancer (CRC). We analyzed polymorphisms rs17817449 (first intron) and rs17818902 (3rd intron) using by PCR-RFLP and then also RT PCR. We found an association of the first intron variant (but not the 3rd one) and BMI in Czech control population. We have detected an association of 1st intron SNP and BMI changes during the intervention study in obese children, but not in obese females. We found a correlation between the risk allele and increased risk of ACS (OR 1.49) in patients with MI. In patients with ESRD was detected association between the risk allele and the risk of disease (OR 1.37). We didn't confirmed the association between rs17817449 and the development of CRC. Representative selected groups of the Czech populations "MONICA" and "HAPPIE" were used as controls. One...
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Molecular basis of endothelial sysfunction: endothelial nitric oxide synthase and heme oxygenase 1 genetic variations
Král, Aleš ; Martásek, Pavel (advisor) ; Baxová, Alice (referee) ; Schneider, Bohdan (referee)
Endothelial dysfunction is a pathologic state characterized by an altered equilibrium among vasodilatory and antithrombotic mediators and vasoconstrictive and prothrombotic mediators produced by the vascular endothelium. Multiple factors induce impaired production or increased consumption nitric oxide (NO), the key mediator of vascular homeostasis, produced by the nitric oxide synthase enzymes (NOS). Endothelial dysfunction represents one of the initial steps in the development of atherosclerosis, a chronic inflammatory disease of the vascular wall. The inducible enzyme heme oxygenase 1 (HO-1) represents one of the main cellular defense mechanisms against increased oxidative stress and decreased NO bioavailability accompanying endothelial dysfunction and atherosclerosis. We studied the genetic determinants of endothelial dysfunction and atherosclerosis by evaluating the association of the G894T endothelial NOS (eNOS) polymorphism and the HO-1 (GT)n promoter polymorphism with coronary artery atherosclerosis severity and risk profile and their evolution during hypolipidaemic treatment. In addition, we searched for genetic variations in exons 25 and 26 of eNOS gene, encoding the C-terminal part of the protein, deemed crucial for proper enzyme function and the 3'- untranslated region crucial for eNOS...
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Trans-species polymorphism in immune genes at wildlife animals
Těšický, Martin ; Vinkler, Michal (advisor) ; Matiašovic, Ján (referee)
Trans-species polymorphism (TSP) is described as the occurrence of identical or similar alleles in related species, excluding cases where the similarity arose by convergence. In TSP the alleles are inherited from ancestor to the descendant species. Neutral TSP is frequent in closely related newly diverged species and it gradually disappears. Considering evolution of immune system and host- pathogen interaction, balanced long-lasted TSP is much more important. Balanced TSP in immune- related genes is maintained by the mechanism of balancing selection and commonly persists for millions of years. In my thesis I map the contemporary knowledge on TSP in immune-related genes, focusing mainly on wild animals. The chief emphasis is given to evolutionary mechanisms influencing the width and age of TSP, distinguishing TSP from other TSP-like evolutionary patterns and methodical difficulties with the assignment of TSP. Presently, most articles dealing with TSP concentrate only on genotyping the Major histocompatibility loci (MHC I and MHC II), especially in the peptide binding region. Our knowledge concerning other immune genes with putative TSP is, therefore, insufficient. Most importantly, this is true for innate immunity genes. More effort should be given to comparative large-scale well-sampled studies...
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Role of the FTO gene in the genetic determination of common multifactorial diseases
Dlouhá, Dana ; Hubáček, Jaroslav (advisor) ; Černá, Marie (referee) ; Rossmeislová, Lenka (referee)
Obesity is a risk factor for development of cardiovascular disease, diabetes type 2 and some cancers. Newly detected genetic risk factor for body weight is the FTO gene ("fat mass and obesity associated"). The aim of this thesis was determine 1) whether the presence of risk alleles correlate with BMI in Czech population and to determine 2) whether there is an association between variants in the FTO gene and risk of myocardial infarction/ acute coronary syndrome (MI/ ACS), 3) renal failure (ESRD), or 4) incidence of colorectal cancer (CRC). We analyzed polymorphisms rs17817449 (first intron) and rs17818902 (3rd intron) using by PCR-RFLP and then also RT PCR. We found an association of the first intron variant (but not the 3rd one) and BMI in Czech control population. We have detected an association of 1st intron SNP and BMI changes during the intervention study in obese children, but not in obese females. We found a correlation between the risk allele and increased risk of ACS (OR 1.49) in patients with MI. In patients with ESRD was detected association between the risk allele and the risk of disease (OR 1.37). We didn't confirmed the association between rs17817449 and the development of CRC. Representative selected groups of the Czech populations "MONICA" and "HAPPIE" were used as controls. One...
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The role of estrogen receptors in prognosis and therapy outcome of breast cancer
Kloudová, Alžběta ; Souček, Pavel (advisor) ; Dračínská, Helena (referee)
Estrogen receptors (ER) are members of nuclear receptor family, which mediate distinct physiological functions after binding a steroid ligand. Apart from that they play a role in many diseases including breast cancer. ER is among proteins routinely evaluated in clinical practice and on the basis of ER expression, patients are treated by endocrine therapy. There are different opinions of the role of ER in cancer cells, but in the future, detection of ER and treatment by ER- and ER-selective ligands could contribute to improvement of cancer therapy. Isoforms, mutations and posttranslational modifications of ER present other important factors, which can influence estrogen signalization and endocrine therapy efficiency and deciphering of their importance for cancer cells could bring better understanding of ER signalization and improvement of the therapy.
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Polymorphism of TLR2/TLR1 and TLR2/TLR6 heterodimers in wild-derived house mouse inbred strains
Bainová, Zuzana ; Vinkler, Michal (advisor) ; Hyršl, Pavel (referee)
Contrary to the classical mouse inbred strains with unnatural genetic variability, wild-derived strains offer a more suitable model for evolutionary immunology. Toll-like receptors (TLRs) belong to initial detectors of invading pathogens. Although TLRs recognise conserved structures they were shown to be polymorphic. This polymorphism is associated with various diseases. In my thesis, I describe variability of Tlr1, 2 and 6 in 24 inbred strains derived from two subspecies of house mouse (Mus m. musculus and M. m. domesticus). These Tlrs exhibit different levels in variability among the strains. In Tlr1 the polymorphic sites are spread along the whole exodomain. Tlr6 is quite conserved (a lower amount of substitutions located far from the binding region and with minor modifications in the amino acid residue properties). Tlr2, on the contrary, contains some substitutions with substantial alternations of residue properties that are located within or nearby the binding region and the subspecies differ at these sites. All alleles of M. m. domesticus and M. m. musculus, except for Tlr1 PWD, Tlr2 STAIL, are phylogenetically separated. The strains and the subspecies vary in the production of IL-1β, IL-12 a NO after stimulation by TLR1, 2 and 6 ligands. This trend is, however, presumably influenced by the effect of...
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The prevalence of chosen polymorphisms of luteinizing hormone receptor gene in Czech population and patients with ovarian hyperstimulation syndrome
Chrudimská, Jana ; Macek, Milan (advisor) ; Schierová, Michaela (referee)
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic potentially life-threatening complication of assisted reproduction techniques (ART). It is caused by an increased sensitivity of ovaries to gonadotropins administered during the controlled ovarian hyperstimulation (COH). Thus, the degree of ovarian response can be gently tuned by genetic polymorphisms of gonadotropins and their receptors. The aim of this study is to ascertain the prevalence of polymorphisms Asn291Ser (rs1470652), Ser312Asn (rs2293275) and insLQ (insertion of leucine and glutamine, rs58356637) in the luteinizing hormone chorionic gonadotropin receptor (LHCGR) gene in 102 Czech fertile men, 149 fertile women and 58 patients with serious grade of OHSS. Detection of the Asn291Ser and Ser312Asn polymorphisms was performed using TaqMan SNP Genotyping Assays. The insLQ variation was detected by the capillary electrophoresis with fluorescence-labeled primers. This study ascertained the prevalence of studied variants in Czech fertile population. Obtained results are in concordance with the majority of data from other European populations. There is no difference in prevalence between control-men and control-women. No relation to the development of OHSS was disclosed. The number of analyzed samples is too small for haplotype analysis. These...
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Relation of fruitfulness in reduction therapy of child obesity at samplet genetics polymophisms
Janoudová, Veronika ; Sedlak, Petr (advisor) ; Daňková, Pavlína (referee)
The aim of the thesis is to analyze the relationship of polymorphisms Ala54Thr FABP2 (protein binding long chain fatty acids in the enterocytes of the small intestine), Gln27Glu B2AR (lipolytic receptor in white adipose tissue) and A-3826G UCP1 (uncoupling protein in the inner membrane of mitochondria in brown adipose tissue) to pursued antropometric and biochemical markers and judge their impact on the success of reducing therapy on children. Association of observed polymorphisms with obesity has already been proven in other studies, the results are inconsistent and most studies have dealt with adults. The study includes of 335 individuals (216 girls and 119 boys) who completed a reduction stay in the Children's hospital of Dr. Filip in Poděbrady. The subjects were studied for anthropometric and biochemical markers at the beginning and at the end of reduction stay. Genetic analysis of polymorphisms were performed with use of PCR-RFLP. Girls Thr/Thr in polymorphism Ala54Thr FABP2 were showing greater thickness of skin fold on abdomen (p=0,009) and higher fat percentage in body composition (p=0,023). Significantly greater reductionof both these markers have been demonstrated (p=0.008, p=0.040). For boys the relationship was observed of homozygote Ala/Ala in a lower weight reduction (p=0,040). In...
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