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27 Publications visible to you, out of a total of 27
Association of schizophrenia with variants of genes that encode transcription factors

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Transcription factors c-Fos, c-Jun, and Ier5 are important regulators of neuronal plasticity and immune response. In the present work, several single nucleotide polymorphisms of the genes that encode … c-Fos-,c-Jun-, and Ier5 (FOS, JUN, and IER5, respectively) were investigated for potential association with schizophrenia. DNA samples obtained from patients with schizophrenia and healthy individuals were genotyped by polymerase chain reaction with allele-specific primers. It was shown that FOS rs1063169, FOS rs7101, JUN rs11688, and IER5 rs6425663 polymorphisms were associated with schizophrenia. In particular, the risk of schizophrenia was decreased in carriers of the minor alleles FOS rs1063169*T, JUN rs11688*A, and IER5 rs6425663*T, but increased in carriers of the FOS rs7101*T minor variant, especially in homozygotes.

Authors: A. S. Boyajyan, S. A. Atshemyan, R. V. Zakharyan

Date Published: 11th Dec 2015

Publication Type: Journal

Risk and Protective Effects of the Complexin-2 Gene and Gene-Environment Interactions in Schizophrenia

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Schizophrenia (SCZ) is a multifactorial chronic and disabling mental disease. The specific genetic variants contributing to disease complex phenotype are largely unknown. Growing amount of evidence … suggested that aberrant synaptic connectivity contributes to SCZ pathogenesis. From this point of view, complexin-2, a presynaptic regulatory protein, represents here a special interest, since it has been recently shown that genetic variants of the CPLX2 gene may affect current cognitive performance in patients with SCZ. A specific objective of this study was to evaluate if tagging single nucleotide polymorphisms (rs3892909, rs1366116) of gene encoding complexin-2 protein (CPLX2) linked to SCZ and to examine their relationships with complexin-2 blood levels. DNA samples of 260 patients with SCZ and 260 sex- and age-matched healthy controls were genotyped for the selected polymorphisms by application of polymerase chain reaction with sequence-specific primers, and concentration of complexin-2 in the blood plasma was determined using the enzymelinked immunosorbent assay. All study subjects were unrelated Armenians. According to the obtained results, in the patients group both the frequency distribution and carriage rate of the CPLX2 rs1366116*T minor allele were higher than in controls. On the contrary, the frequency distribution and carriage rate of the CPLX2 rs3892909*T minor allele in control group were higher than in patients. This data suggested that the presence of the CPLX2 rs1366116*T allele increases susceptibility to SCZ, whereas the rs3892909*T allele of the CPLX2 decreases the risk of SCZ. Furthermore, we found that CPLX2 rs1366116*T heterozygosity is associated with earlier disease onset. No difference between complexin-2 plasma levels in patients and controls and no significant interaction between complexin-2 plasma levels and CPLX2 genotypes in both groups were observed. In summary, we concluded that the CPLX2 rs1366116*T variant represents a risk factor of SCZ, and that, at the same time, the CPLX2 rs3892909*T variant is protective against SCZ.

Authors: Roksana Zakharyan, Sofi Atshemyan, Anna Boyajyan

Date Published: 24th Oct 2014

Publication Type: Journal

Nerve growth factor and its receptor in schizophrenia

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Promising studies suggest that defects in synaptic plasticity detected in schizophrenia may be linked to neurodevelopmental and neurodegenerative abnormalities and contribute to disease-associated … cognitive impairment. We aimed to clarify the role of the synaptic plasticity regulatory proteins, nerve growth factor (NGF) and its receptor (NGFR) in the pathogenesis of schizophrenia by comparative analysis of their blood levels and functional single nucleotide polymorphisms (SNPs) in genes encoding these proteins (NGF and NGFR) in schizophrenia-affected and healthy subjects. Relationships between the selected SNPs' genotypes and NGF and NGFR plasma levels were also assessed. Our results demonstrated a positive association between schizophrenia and the NGF rs6330 as well as the NGFR rs11466155 and rs2072446 SNPs. Also, a negative association between this disorder and NGF rs4839435 as well as NGFR rs734194 was found. In both, haloperidol-treated and antipsychotic-free patients decreased blood levels of the NGF and NGFR were found, and a positive interrelation between rs6330 and rs2072446 carriage and decreased NGF and NGFR levels, respectively, was revealed. In conclusion, our results demonstrate association of schizophrenia with the rs6330, rs4839435 and rs734194, rs11466155, rs2072446 as well as with the decreased blood levels of corresponding proteins. Our findings indicate the implication of alterations in NGFR and NGFR genes in schizophrenia, particularly, in defects of synaptic plasticity. Furthermore, the data obtained suggests that at least in Armenian population the NGF rs6330*T and NGFR rs11466155*T, rs2072446*T alleles might be nominated as risk factors, whereas the NGF rs4839435*A and NGFR rs734194*G alleles might be protective against developing schizophrenia.

Authors: Roksana Zakharyan, Sofi Atshemyan, Anaida Gevorgyan, Anna Boyajyan

Date Published: 1st Jun 2014

Publication Type: Journal

Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke

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Epidemiologic, clinical and experimental data indicates that a majority of brain disorders including schizophrenia (SCZ), posttraumatic stress disorder (PTSD), and ischemic stroke (IS) are multifactorial … disorders with strong and complex genetic component. Identification of all genetic variations associated with these disorders may sufficiently contribute to understanding of their basic pathomechanisms and encourage development of new innovative approaches to their early diagnosis and treatment. The aim of this review article is to provide overview of our recent studies on evaluation of potential association of SCZ, PTSD and IS with functional single nucleotide polymorphisms (SNPs) of synaptic plasticity and apoptosis regulatory genes in Armenian population. Here, our attention was focused on genes encoding netrin G1 (NTNG1), brain-derived neurotrophic factor (BDNF), complexin-2 (CPLX2), nerve growth factor (NGF) and its receptor (NGFR), annexin family proteins - annexin A5 and annexin A11 (ANXAV, ANXA11), and B-cell lymphoma 2 (Bcl-2) family proteins - Bcl-2 proper and Bcl-2-associated X protein (BCL2, BAX). Genomic DNA samples of diseased and healthy individuals were genotyped for a number of SNPs of the mentioned genes using polymerase chain reaction with sequence-specific primers (PCR-SSP). The significance of differences in genotype and allele frequencies and minor allele carriage between patients and healthy control subjects was determined using Pearson’s Chi-square test. P-values less than 0.05 were considered statistically significant. Significant associations were found between: (1) SCZ and BDNF rs6265, CPLX2 rs1366116, rs3892909, NGF rs6330, rs4839435, NGFR rs734194, rs11466155, rs2072446, ANXAV rs11575945, BAX rs1057369 SNPs; (2) PTSD and CPLX2 rs1366116, BCL2 rs956572 SNPs; (3) IS and NTNG1 rs628117, CPLX2 rs1366116, ANXAV rs11575945 SNPs. The obtained results indicated the involvement of genetically determined alterations in synaptic plasticity and apoptosis in pathomechanisms of SCZ, PTSD and IS. The minor T allele of the CPLX2 gene rs1366116 polymorphism represents risk factor for all studied diseased conditions indicating important functional significance of this genetic variation in maintenance of synaptic plasticity. Another important conclusion of these studies is that minor alleles of some polymorphic variants of genes, encoding synaptic plasticity and apoptosis regulatory proteins, may play a protective role relative to SCZ decreasing the risk for development of this disorder. In summary, our studies emphasize the important contribution of changes in synaptic plasticity and apoptosis regulation to pathomechanisms of SCZ, PTSD, and IS as well as significant input of genetic factors to these changes.

Authors: Anna Boyajyan, Ani Stepanyan, Diana Avetyan, Hovsep Ghazaryan, Sofi Atshemyan, Roksana Zakharyan, Kristina Pirumyan, Gohar Tsakanova

Date Published: 30th May 2014

Publication Type: Journal

Brain-derived neurotrophic factor blood levels are decreased in schizophrenia patients and associate with rs6265 genotypes

Abstract (Expand)

Objectives: A growing number of studies implicate brain-derived neurotrophic factor (BDNF), an important promoter of synaptic transmission and neural plasticity, in the pathogenesis of schizophrenia. … However, the existing data are controversial, that may reflect population differences between studied groups. Design and methods: In the present study we performed a comparative analysis of BDNF plasma levels and its relation with rs6265 (G196A; Val66Met) polymorphism of BDNF gene (BDNF) in schizophrenia-affected and healthy subjects (controls) of the Armenian population. To check the influence of antipsychotics on BDNF plasma levels both medicated and non-medicated patients were involved in this study. Patients with paranoid form of schizophrenia chronically treated with typical antipsychotics (n=103), age- and sex-matched controls (n=105), and 25 antipsychotic-naive first-episode schizophrenia patients were involved. The levels of BDNF in the blood plasma were measured with a solid-phase enzyme-linked immunosorbent assay. Results: Decreased plasma levels of BDNF in both medicated and non-medicated schizophrenia patients compared to controls were observed. No significant difference in BDNF levels between medicated and non-medicated patients was detected. It was also detected that, compared to individuals homozygous for the standard allele (G/G) of rs6265, carriers of the rs6265 minor allele (A/G+A/A), which is significantly more frequent in schizophrenia patients than in controls, had decreased BDNF levels. Conclusions: The data obtained suggested that the pathogenesis of schizophrenia is characterized by genetically predetermined decreased blood levels of BDNF. These results indicated that genetically determined alterations of neuroimmune modulators may be among the risk factors of schizophrenia and contribute to disease-specific pathologic changes in functional activity of both the neuronal synaptic plasticity and the immune system. Keywords: Brain-derived neurotrophic factor; Plasma levels; Schizophrenia; rs6265 Polymorphism.

Authors: Roksana Zakharyan, Anna Boyajyan

Date Published: 5th Apr 2014

Publication Type: Journal

Inflammatory cytokine network in schizophrenia

Abstract (Expand)

Objectives: The purpose of this review is to analyse, sum up and discuss the available literature on the role of inflammation and inflammatory cytokines in the pathogenesis of schizophrenia. Methods: …: An electronic literature search of peer-reviewed English language articles using Pubmed was undertaken. These articles together with those published by us provided the background for the present review. Results: An overview of the available literature on this issue clearly demonstrated the alterations in mRNA and protein expression levels of several proinflammatory and chemotactic cytokines in patients with schizophrenia. Importantly, some of these changes are genetically determined. It was noteworthy that, depending on the study population, some variations of the data obtained are detected. Conclusions: Altered inflammatory cytokine production, both genetically and environmentally determined, is implicated in schizophrenia and contributes to disease-associated low-grade systemic inflammation. Proinflammatory and chemotactic cytokines and their receptors may represent additional therapeutic targets for treatment of schizophrenia.

Authors: Roksana Zakharyan, Anna Boyajyan

Date Published: 16th Sep 2013

Publication Type: Journal

Markers of apoptotic dysfunctions in schizophrenia

Abstract (Expand)

According to the modern concepts, alterations of apoptosis and its genetic regulation are associated with the etiopathogenesis of schizophrenia, which is observed at both the brain and peripheral blood … levels. However, studies of this phenomenon are at the initial stage, and the molecular and cellular mechanisms that underlie the anomalies of the processes of apoptotic cell death in schizophrenia are unclear. In the present study, we determined the levels of apoptotic markers, annexin A5 and H-ficolin proteins, in the sera of patients with chronic and first-episode schizophrenia and healthy subjects to test the proposed relationship between schizophrenia and the rs11575945 (−1C/T) single-nucleotide substitution (functional polymorphism) of Kozak consensus sequence in the regulatory region of the annexin A5 gene. Methods of a solid-phase enzyme-linked immunosorbent assay and polymerase chain reaction with allele-specific primers were used. It was shown that the pathogenesis of schizophrenia is characterized by an increased rate of apoptosis, which is more pronounced in the case of the first-episode neuroleptic-free patients than in the case of chronic patients that receive typical neuroleptic haloperidol. It was also shown that the rs11575945 polymorphism of the annexin A5 gene is associated with schizophrenia, and its minor allele is responsible for higher levels of the annexin A5 protein in the blood and represents one of the risk factors for the development of this disease.

Authors: A. S. Boyajyan, A. S. Chavushyan, R. V. Zakharyan, G. M. Mkrtchyan

Date Published: 15th Aug 2013

Publication Type: Journal

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