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    Association analysis of Epworth Sleepiness Scale (ESS) scores with serotonin transporter (5-HTT- LPR, 5-HTT-VNTR) and circadian (PER3-VNTR) genes
    (Thieme Medical Publ Inc, 2022) Ozen, Filiz; Yegin, Zeynep; Saglam, Zuhal Aydan; Yavlal, Figen; Koc, Haydar; Ulasoglu, Celal
    Excessive daytime sleepiness (EDS) is a common complaint encountered in clinical practice with serious consequences both for individual and society since it can increase the ratio of motor vehicle accidents, work-related incidents, and deaths. Moreover, it also manifests less serious individual consequences. This study aimed to investigate the potential role of PER3-VNTR, 5-HTT-LPR, and 5-HTT-VNTR in terms of constituting liability to EDS. Two hundred eighteen participants (93 complaining about daytime sleepiness and 125 individuals with no serious complaint) were recruited in the study. General daytime of sleepiness was quantified with Epworth sleepiness scale (ESS). DNA extractions were performed from collected blood samples with standart salting-out procedure and genotyped. ESS scores displayed difference between individuals suffering from sleep disturbances and other individuals with values of 12.75 +/- 4.55 and 6.34 +/- 4.26, respectively. PER3VNTR and 5-HTT-LPR genotypes did not display association with mean ESS scores. However, 5-HTT-VNTR genotypes showed significant association with mean ESS scores; individuals with 10/10 genotypes had the highest ESS score reflecting this genotype as a liability factor for EDS. We strongly recommend further studies based on circadian/serotonin pathway genes in different populations to reach to a consensus and highlight sleep genetic marker genes which then can be the future targets of pharmacological treatment studies for sleep problems.
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    Expression profiles of proto-oncogene TWIST1 and tumor metastasis suppressor gene LASS2 in bladder cancer
    (C M B Assoc, 2018) Yegin, Zeynep; Aydin, Oguz; Koc, Haydar; Buyukalpelli, Recep
    Transcription factor proto-oncogene TWIST1 and tumor metastasis suppressor gene LASS2 have been reported to be involved in various carcinomas but their expression profiles and prognostic significances in bladder cancer are largely unknown. We aimed to determine these genes' expression levels both at mRNA and protein level in bladder cancer. mRNA expression levels of TWIST1 and LASS2 genes were examined using real-time quantitative PCR (qPCR) in human bladder tumors and paired normal adjacent tissues obtained from 44 patients. Protein expression profiles of both genes were detected by immunohistochemical staining in formalin-fixed and paraffin-embedded tissues from the same patients. The expression profiles of TWIST1 mRNA in bladder tumors were significantly lower than the normal adjacent tissues and linked to both the stage and the grade. The expression profiles of LASS2 mRNA in bladder tumors were also significantly lower than the normal adjacent tissues reflecting the potential tumor suppressor profile of the gene, independently from stage or grade. By immunohistochemistry, TWIST1 and LASS2 positive expression rates were found as 14.3% (6/42) and 38.1% (16/42), respectively. As potential molecular markers for bladder carcinoma, both TWIST1 and LASS2 transcripts seem to play role during the tumorigenesis and development of bladder cancer. Lack of a functional link and/or weak inverse link between TWIST1 and LASS2 transcripts and immunohistochemical findings may reflect the potential associations of transcription regulation mechanisms and merit further investigations. To the best of our knowledge, this is the first report investigating the combined expression profile of TWIST1 and LASS2 in bladder cancer both at mRNA and protein level.
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    For whom the circadian clock ticks? Investigation of PERIOD and CLOCK gene variants in bipolar disorder
    (Taylor & Francis Inc, 2021) Yegin, Zeynep; Sarisoy, Gokhan; Erguner Aral, Ayse; Koc, Haydar
    Clock genes play significant roles in the regulation of circadian rhythms, which are thought to be involved in the pathophysiology of neurodegenerative and psychiatric diseases. We aimed to investigate the association of five gene polymorphisms (PER3 VNTR (rs57875989), PER2 rs2304672, CLOCK rs1801260, CLOCK rs10462028, CLOCK rs11932595) with PCR-based methods as potential risk factors in bipolar disorder (BD). We used a multiple testing methodology in BD patients (n = 121) and healthy control individuals (n = 121) of Turkish descent to analyze the effects of these gene variants both as risk factors for the disorder and for the evaluation of these variants in the patient group with multiple subscales. We evaluated the circadian rhythm disturbances and seasonal variations in mood and behavior in BD patients using the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) and Seasonal Pattern Assessment Questionnaire (SPAQ) to enlighten the possible links between these scores and the studied circadian gene variants. The results of our study revealed significant associations: PER3 VNTR (rs57875989) 5/5 repeat genotype displayed a protective effect against BD when compared with 4/4 repeat genotype. Moreover, patients with PER3 VNTR 5/5 repeat genotype displayed a higher ratio of hypomania. PER2 rs2304672 G allele frequency increased the risk for BD. There was no association in terms of genotype/allele frequency comparisons between patients and controls for CLOCK gene variants. However, significant associations were found in patients in terms of clinical and behavioral patterns such as mean age at disease onset and BRIAN total scores enabling some risk stratifications for patients. Our results indicate the significance of circadian gene variants in BD, which need to be confirmed in different studies with larger samples. Thus, the possible endophenotypes of BD can be enlightened and advanced chronotherapeutics approaches can be manipulated in the future for clinical benefit.
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    Investigation of the functional vesicular monoamine transporter 1 (VMAT1/SLC18A1) Thr136Ile gene variant in bipolar disorder
    (Sociedad Espanola de Psiquiatria Biologica (SEPB), 2022) Yegin, Zeynep; Sarisoy, Gokhan; Erguner Aral, Ayse; Koc, Haydar
    Background and objectives: Bipolar disorder (BD) is an episodic and recurrent mood disturbance ranging from mania to severe depression. Because of the heterogeneity of psychiatric disorders, enlightening the possible molecular risk drivers is crucial. Vesicular monoamine transporter 1 (VMAT1) is an important candidate gene to study the underlying molecular mechanisms in BD pathogenesis since it has a significant role in the packaging of monoaminergic neurotransmitters into presynaptic storage vesicles. The aim of this study was to ascertain whether functional and evolutionarily important variant of VMAT1 gene (Thr136Ile (rs1390938)) would affect the susceptibility of the individuals to BD in a Turkish population. Method: One hundred twenty BD patients and one hundred one healthy control individuals were recruited for the study. Samples were genotyped using PCR-RFLP method to detect VMAT1 gene variant (Thr136Ile (rs1390938)). Results: Contrary to our expectations, VMAT1 Thr136Ile (rs1390938) gene variant was not associated with BD in our population. There was also no relationship between VMAT1 genotypes and some clinically significant parameters in BD patients. Conclusion: Our data showed no association between VMAT1 Thr136Ile (rs1390938) and BD in Turkish population. We strongly recommend the analysis of this variant in other populations to draw a precise conclusion about the role of this variant in bipolar disorder. Further large-scale research for the other variants of VMAT1 is also required to clarify the strong hypothesis focused on VMAT1 variants in the development of neuropsychiatric disorders. © 2022
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    Lack of association between MAOA-uVNTR variants and excessive daytime sleepiness
    (Springer-Verlag Italia Srl, 2017) Ozen, Filiz; Yegin, Zeynep; Yavlal, Figen; Saglam, Zuhal Aydan; Koc, Haydar; Berber, Ismet
    Sleep disorders are highly prevalent in the population and have dramatic health, social, and economic impacts. However, their treatments may remain symptomatic due to ignorance of molecular factors which may provide fundamental insights into the neurological bases of sleep. Excessive daytime sleepiness (EDS) is a common complaint encountered in neurological practice with significant effects both on individuals and on society. We aimed to investigate the role of monoamine oxidase A (MAOA) as a candidate gene in EDS. Epworth sleepiness scale (ESS) was applied to 221 subjects who were also genotyped for MAOA upstream variable number of tandem repeats (MAOA-uVNTR). Patient group displayed higher ESS values (mean 12.67) when compared with the control group (mean 6.38). However, MAOA-uVNTR genotypes did not show a significant association with ESS scores neither on women nor on men. Finally, these data suggest further replications in different populations. Moreover, the investigation of some other genes together with MAOA and/or some possible regulatory molecular mechanisms may offer a more comprehensive approach in the role of genetic factors contributing to EDS.
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    Role of miRNA Gene Variants (miR-22 and miR-155) as the Factors Affecting Susceptibility to Panic Disorder
    (Korean Coll Neuropsychopharmacology, 2024) Yegin, Zeynep; Sarisoy, Gokhan; Uzun, Ahmet; Koc, Haydar
    Objective: Variants within genes encoding microRNAs (miRNAs) may alter the expression of both miRNAs and their target genes, thus contributing to the etiology of psychiatric disorders. The involvement of miRNAs in neuronal differentiation and synaptic plasticity supported this hypothesis. We aimed to investigate the links between miR-155 rs767649/miR-22 rs8076112 and the risk of panic disorder (PD) in a sample of Turkish population. Methods: In this experimental study, 134 PD patients and 140 healthy controls were recruited. Genotyping was carried out using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. To evaluate PD phenotypes, Panic Disorder Severity Scale (PDSS) was also administered to patients to clarify possible associations between the scale and risk variants analyzed. Results: The genotype analysis of miR-155 rs767649 did not show an association with PD risk and it was not related to the disease severity. For miR-22 rs8076112 variant, a statistically significant association was determined; CC genotypes were lower in patients compared to controls. Logistic regression analysis proved the highly protective effect (80.4%) of CC genotype against PD (p = 0.041; OR = 0.196, 95% CI = 0.041-0.934). Though its significance in disease liability, miR-22 rs8076112 was not associated with the disease severity. Conclusion: Our findings firstly report the combined analysis of miR-155 rs767649 and miR-22 rs8076112 in PD in terms of both disease susceptibility and severity. These findings await replication in independent cohorts with enrichment of other miRNA gene variants. Thus, certain miRNAs and their target genes involved in the etiology and phenotypes of PD could be enlightened.