A Single Nucleotide Polymorphism Within Molybdenum Cofactor Sulfurase Gene Is Associated With Neuropsychiatric Conditions.

BACKGROUND: Molybdenum cofactor sulfurase (MOCOS) is an enzyme participating in purine metabolism. The aim of current study was to evaluate the role of a single nucleotide polymorphism (SNP) in the coding gene (rs594445) in mood disorders and methamphetamine addiction. METHODS: This SNP was genotyped in 200 persons with methamphetamine addiction, 85 patients with bipolar disorder 1 (BP1), 78 patients with BP2, 33 patients with major depressive disorder (MDD) and 200 age-/sex-matched normal subjects using the tetra-primer amplification-refractory mutation system (ARMS)-PCR technique. RESULTS: The rs594445 was associated with methamphetamine addiction in co-dominant model [A/A vs C/C: OR (95% CI) = 0.466 (0.252-0.864), P-value = 0.014; C/A vs C/C: OR (95% CI) = 0.641 (0.418-0.981), P-value = 0.04]. This SNP was also associated with this trait in dominant model [OR (95% CI) = 0.591 (0.398-0.879), P-value = 0.009]. The A allele of rs594445 had a protective role against methamphetamine addiction [A vs C: OR (95% CI) = 0.645 (0.48-0.866), P-value = 0.004]. The rs594445 was associated with BP1 in co-dominant model [C/A vs C/C: OR (95% CI) = 0.423 (0.230-0.778), P-value = 0.005]. However, the associations were insignificant in other inheritance models. CONCLUSION: Finally, there were no significant associations between the mentioned SNP and risk of BP2 or MDD in any inheritance model. The present project highlights the role rs594445 in two psychiatric conditions and implies the presence of common genetic factors for these disorders.

STAT5a and STAT6 gene expression levels in multiple sclerosis patients.

Multiple sclerosis (MS) is a complex inflammatory, autoimmune disease of the central nervous system (CNS). The disease pathogenesis is not well defined yet. Cytokines have an important role in inflammation as characteristic feature of the disease. Janus kinase/signal transducers and activators of transcriptions (JAK/STAT) family promote cytokine-mediated cell activation. Failure in the JAK/STAT signaling pathway is associated with the pathological outcome in MS. In this study, we compared the expression levels of STAT5a and STAT6 genes in the blood of 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls by Taqman Quantitative Real-Time PCR in patients and healthy control group. We found that STAT5a expression was significantly down-regulated (p = .049), whereas STAT6 gene expression was significantly up-regulated (p = .046) in MS patients compared with controls. Moreover, there was significant correlation between the STAT6 gene expression and Kurtzke Expanded Disability Status Scale (EDSS) criterion. However, no significant correlation was demonstrated between the expression of STAT5a gene and clinical findings. Furthermore, there was not significant correlation between expression levels of STAT5a and STAT6 genes. Our findings suggest that STAT5a and STAT6 dysregulation may have a critical role in modification of immune responses leading to imbalance between Th2- and Th1-related cytokines. However, the mechanisms underlying it still remain to be elucidated. Future studies are needed to explore the role of STAT5a and STAT6 as prognostic biomarkers in research, design of experimental therapies or clinical settings of the MS.

Vaccinia Related Kinase 2 (VRK2) expression in neurological disorders: schizophrenia, epilepsy and multiple sclerosis.

BACKGROUND: Schizophrenia (SCZ), epilepsy and Multiple Sclerosis (MS) are neurological disorders with increasing prevalence disturb the patients' lives and are regarded as burdens to the society. As multifactorial disorders, genetic susceptibility factors are involved in their pathogenesis. The Vaccinia-Related Kinase 2 (VRK2) gene codes for a serine threonine kinase recently reported to be contributed in the pathogenesis of some neurological disorders. In the present case-control study we compared the VRK2 gene expression in peripheral blood samples from SCZ, epilepsy and MS patients with normal subjects. METHOD: A total of 300 subjects comprising 50 patients in each disease category (SCZ, epilepsy and MS) as well as 150 healthy individuals (50 matched controls for each disorder) participated in the current study. RESULT: The VRK2 blood mRNA expression level was measured using the TaqMan real time PCR. The results demonstrated significant down-regulation of VRK2 gene in SCZ (P<0.0001), epilepsy (P=0.008) and MS (P=0.029) compared with the healthy subjects. CONCLUSION: Consequently, VRK2 is suggested as a candidate gene for neurological disorders through its role in signaling pathway, the neuronal loss and stress response.

Ecotropic Viral Integration Site 5 (EVI5) variants are associated with multiple sclerosis in Iranian population.

BACKGROUND: Multiple sclerosis (MS) is a multifactorial disorder with immunological basis. Numerous genetic and environmental factors contribute in its pathogenesis. Several genetic loci have been shown to be associated with MS risk. Among genes whose participation in MS has been evaluated is Ecotropic Viral Integration Site 5 (EVI5). EVI5 is a common site of retroviral integration with a possible role in T-cell lymphomagenesis. METHODS: In the current study, we aimed to confirm association of the single nucleotide polymorphisms (SNPs) within EVI5 gene with MS in 410 relapsing-remitting MS patients and 410 controls from Iranian population. The rs6680578, rs10537781 and rs11810217 genotypes were defined by amplification-refractory mutation system (ARMS)-PCR method. RESULTS: The allele and genotype frequencies of rs6680578 and rs11810217 were not significantly different between cases and controls. However, in the rs10735781 the GG genotype was significantly associated with MS risk in recessive (P = 0.03, OR (95%CI) = 1.84 (1.05-3.19)) and co-dominant models (P = 0.02, OR 95%CI) = 1.90 (1.08-3.35)). In addition, T G T haplotype (rs6680578, rs10735781 and rs11810217 respectively) was associated with MS risk while T C C, A G T and A C T had a protective effect against MS. CONCLUSION: The results of the current study provide further evidences for participation of EVI5 in MS pathogenesis.

Valproic acid may exerts its cytotoxic effect through rassf1a expression induction in acute myeloid leukemia.

In acute myeloid leukemia (AML), despite the acceptance of standard intensive chemotherapy as an optimal induction regimen for all age groups, in the elderly patients, the best treatment should meet the challenge of multiple factors like age, comorbidities, and cytogenetics, making them ineligible for standard induction chemotherapy. Using the current low-intensity therapies like decitabine, azacitidine, and low-dose cytarabine as a single arm, outcomes for these patients remain poor. As a histone deacetylase inhibitor valproic acid (VPA) exhibit anticancer activity by triggering apoptosis, the mechanism of which is not yet completely clarified. To explore the possible connection between VPA treatment and the Hippo pathway as an apoptosis stimulating route, we also explore the expression of major components of this pathway and for the first time we postulate a relationship between VPA treatment and cell death induction through RASSF1A expression induction. Furthermore, we demonstrate that autophagy inhibition by chloroquine (CQ) significantly augmented the cytotoxic effect of VPA on AML cells, especially in those with unfavorable and normal karyotype. Regarding that VPA and CQ are well-tolerated drugs and our presumptive results of usefulness of VPA + CQ in three cytogenetic risk groups of AML, this combinatorial therapy could represent an attractive treatment option for older AML patients unfit for intensive therapy.