Genetic Polymorphisms in miR-137 and Its Target Genes, TCF4 and CACNA1C, Contribute to the Risk of Bipolar Disorder: A Preliminary Case-Control Study and Bioinformatics Analysis.

Accumulating evidence has suggested that miR-137 and its target genes, CACNA1C, and TCF4, are amongst the most robustly implicated genes in psychiatric disorders. This preliminary study is aimed at investigating the effects of genetic variations in miR-137 (rs1625579A/C), TCF4 (rs1261084C/T), and CACNA1C (rs10774053A/G and rs10466907G/T) on BD susceptibility. We recruited 252 BD patients and 213 healthy subjects as the control group. Genotyping was performed using PCR-RFLP and ARMS-PCR methods. Enhanced risk of BD was found under the codominant homozygous, dominant, and allelic models of TCF4 rs1261084C/T, codominant homozygous and allelic models of CACNA1C rs10466907G/T polymorphisms, as well as codominant homozygous, dominant, recessive, and allelic models of the CACNA1C rs10774053A/G. Moreover, both TT/AG/GT/AA and TT/GG/GT/AC genotype combinations strongly increased the risk of BD in the participants. The bioinformatics analyses revealed that rs1261084C/T and rs10466907G/T created and disrupted binding sites of some miRNAs in the 3'-untranslated region of TCF4 and CACNA1C genes. In contrast, the rs10774053A/G created a new binding site for a major splicing factor and might have an effective role in the function of the CACNA1C protein. We have found that all the studied SNPs are positively associated with BD susceptibility. Replicated studies on different ethnicities are required to confirm these findings.

Long noncoding RNA HOTAIR polymorphisms and susceptibility to bipolar disorder: a preliminary case-control study.

Recent studies have shown that long noncoding RNAs contribute to the pathogenesis of bipolar disorder (BD). In this study, we genotyped four HOX Transcript Antisense Intergenic RNA (HOTAIR) gene polymorphisms to investigate if these variations could affect the risk of BD and its clinical subtypes. A total of 357 subjects, comprised of 194 BD patients and 163 age-matched healthy controls, were enrolled. Genotyping was carried out using PCR-RFLP and ARMS-PCR methods. We detected significant associations between the HOTAIR gene rs1899663 G/T, rs12826786 C/T, rs4759314 A/G, and rs920778 C/T polymorphism and the risk of BD under allelic, recessive, dominant, and codominant contrasted genetic models. The CT genotype of rs920778 C/T, GT genotype of rs1899663 G/T, and CT genotype of rs12826786 C/T polymorphisms enhanced the risk of BD type II (BDII). In contrast, the GG genotype of rs4759314 A/G polymorphism significantly diminished BDII risk by 83%. A positive association was noticed between CTTA and CTCG haplotypes of rs920778/rs1899663/rs12826786/rs4759314 and BD risk. Our findings reveal an interactive effect of HOTAIR polymorphisms on the development of BD and its subtypes. Further functional studies are needed to elucidate the role of these variations on HOTAIR expression and epigenetic status.

Relationship between GABRB2 gene polymorphisms and schizophrenia susceptibility: a case-control study and in silico analyses.

PURPOSE: Converging evidence has recently established the significance of γ-aminobutyric acid neurotransmitter (GABA) system in the development of schizophrenia (SCZ). We aimed to determine the association of two markers of the GABAA receptor ß2 subunit gene (GABRB2), rs12187676 G/C and rs1816072 T/C, with the risk of SCZ in Iranian population. MATERIALS AND METHODS: In this case-control study, 190 patients with SCZ and 200 healthy controls were recruited from December 2018 to February 2020. Genotyping was done using the Tetra-ARMS-PCR technique. In silico analyses were performed to determine the potential effects of the variants. RESULTS: The C allele and genotypes of codominant CC vs.TT and CT vs.TT, dominant TT vs. TC + CC, recessive TT + TC vs. CC of rs1816072 polymorphism, as well as codominant CC vs. GG and recessive GG + GC vs. CC genetic models of rs12187676 polymorphism were significantly associated with SCZ susceptibility. Compared to the TC/GC model, we have found that the TC/CC combination significantly increased the risk of SCZ by 4.32 fold while the TT/GG combination conferred a protective role against SCZ. Haplotypes analysis indicated that GABRB2 polymorphisms are in weak linkage disequilibrium with each other (LD = 0.1). However, bioinformatics analyses predicted that these polymorphisms do not have significant effects on the secondary structure and the splicing of GABRB2-mRNA. CONCLUSIONS: We found that intronic GABRB2 polymorphisms were associated with SCZ risk in a sample of the Iranian population. These findings provided proof of concept for the involvement of the GABAergic neurotransmission system in SCZ development. These observations should be validated across other ethnicities and clinical subtypes.

Functional Variants of miR-143 Are Associated with Schizophrenia Susceptibility: A Preliminary Population-Based Study and Bioinformatics Analysis.

Single nucleotide polymorphisms within genes encoding microRNAs may alter the expression of microRNAs and their target genes, contributing to the etiology of psychiatric disorders. We aimed to investigate the link between rs4705342T/C and rs4705343T/C polymorphisms in the promoter region of miR-143 and the risk of schizophrenia (SCZ) in a sample of an Iranian population. In this experimental study, a total of 398 subjects were recruited. Genotyping carried out using allele-specific PCR (AS-PCR) method. Different bioinformatics databases and Cytoscape V3.4.0 software were used for the analysis of the gene-miRNA interaction network. The genotypic analysis of rs4705342C/T showed that CC genotype in the co-dominant model significantly decreased the risk of SCZ (p < 0.001). Also, a significantly reduced risk of SCZ was observed under allelic (p < 0.001), dominant (p = 0.007), and recessive (p = 0.001) models of this variant. As regards rs4705343T/C, significantly enhanced risk of SCZ was found under the co-dominant CC (p = 0.01) and recessive (p = 0.007) contrasted genetic models. For this variant, the C allele conferred an increased risk of SCZ by 1.41 fold. Haplotype analysis showed that the Crs4705342 Trs4705343 haplotype significantly diminished SCZ susceptibility. The result of the bioinformatics analysis showed that miR-143, as a critical miRNA, targets ERK5, ERBB3, HK2, and PKCε, the four major genes involved in SCZ development. Our findings suggest that these two polymorphisms might affect SCZ susceptibility. Elucidating the precise regulatory mechanisms of gene expression in the development of SCZ will help researchers discover a novel target for therapeutic interventions.

Impact of Proliferator-Activated Receptor γ Gene Polymorphisms on Risk of Schizophrenia: A Case-Control Study and Computational Analyses.

Objective: Schizophrenia (SCZ) is a common psychiatric disorder characterized by a complex mode of inheritance. Peroxisome proliferator-activated receptor-γ (PPARG) mainly regulates lipid and glucose metabolisms while it is constitutively expressed in rat primary microglial cultures. This preliminary study was aimed to investigate the relationship of two polymorphisms in the PPARG gene, rs1801282 C/G, and rs3856806 C/T, to the risk of SCZ in the southeast Iranian population. Method : A total of 300 participants (150 patients with SCZ and 150 healthy controls) were enrolled. Genotyping was done using the amplification refractory mutation system polymerase chain reaction (ARMS-PCR) technique. Computational analyses were carried out to predict the potential effects of the studied polymorphisms. Results: A significant link was found between genotypes of rs1801282 and SCZ susceptibility. The G allele of rs1801282 in CG and GG form of the codominant model increased the risk of SCZ by 2.49 and 2.64 folds, respectively. With regards to rs3856806, enhanced risk of SCZ was also observed under different inheritance models except for the overdominant model. Also, the T allele of rs3856806 enhanced the risk of SCZ by 3.19 fold. Computational analyses predicted that rs1801282 polymorphism might alter the secondary structure of PPARG-mRNA and protein function. At the same time, the other variant created the binding sites for some enhancer and silencer motifs. Conclusion: Our findings showed that PPARG rs1821282 and rs3856806 polymorphisms associate with SCZ susceptibility. Replication studies in different ethnicities with a larger population are needed to validate our findings.

Relationship between Single Nucleotide Polymorphisms of GRHL3 and Schizophrenia Susceptibility: A Preliminary Case-Control Study and Bioinformatics Analysis.

Grainyhead-like (GRHL) transcription factors were recently linked to the etiology of neural tube defects (NTDs). Overlapping patterns in the variation of schizophrenia (SCZ) incidence with that of NTDs suggests the presence of common etiological risk factors. This preliminary study was designed to examine the relationship between two missense variants of GRHL3 gene (rs2486668C/G and rs545809A/T) and SCZ susceptibility among Iranians. Three hundred ninety subjects (192 patients confirmed with SCZ, and 198 healthy controls) were enrolled and genotyped. Statistical and bioinformatics analyzes were performed to determine the effects of the variants. In silico analyzes were performed to determine the effects of the variants on the secondary structure of GRHL3 protein and prediction of silencer motifs for each variation. Statistically significant differences were observed between the studied groups under codominant AA, dominant AT+AA, and recessive AA genetic contrast models for rs545809A/T. The presence of the A allele of rs545809A/T enhanced SCZ risk by 2.33 fold. In contrast, rs2486668C/G was not linked to SCZ susceptibility (P > 0.05). Bioinformatics analysis revealed that both missense SNPs caused substantial changes in the secondary structure of GRHL3-mRNA. Screening of the flanking sequences of rs545809A/T predicted silencer motifs for this SNP. Our results demonstrated that the rs545809A/T of GRHL3 gene could affect the risk of SCZ in Iranian populations. Replication studies are warranted to confirm these results.

Polymorphism in the 3'-UTR of LIF but Not in the ATF6B Gene Associates with Schizophrenia Susceptibility: a Case-Control Study and In Silico Analyses.

Schizophrenia (SCZ) is a multifactorial disorder caused by environmental and genetic factors. Studies have shown that various single-nucleotide polymorphisms (SNPs) in the binding sites of microRNAs contribute to the risk of developing SCZ. We aimed to investigate whether the variants located in the 3'-UTR region of LIF (rs929271T>G) and ATF6B (rs8283G>A) were associated with increased susceptibility to SCZ in a population from the south-east of Iran. In this case-control study, a total of 396 subjects were recruited. SNPs were genotyped via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Genotyping results showed that the G allele of rs929271 significantly increased the risk of SCZ (OR = 1.58 95%CI = 1.19-2.10, p = 0.001). As for rs929271, the GG genotype of co-dominant (OR = 2.54 95%CI = 1.39-4.64, p = 0.002) and recessive (OR = 2.91 95%CI = 1.77-4.80, p < 0.001) models were strongly linked to SCZ. No significant differences were observed between rs8283 polymorphism and predisposition to SCZ. In silico analyses predicted that rs929271 might alter the binding sites of microRNAs, which was believed to have an unclear role in the development of SCZ. Moreover, rs929271 polymorphism changed the LIF-mRNA folding structure. These findings provide fine pieces of evidence regarding the possible effects of LIF polymorphism in the development of SCZ and regulation of the LIF gene targeted by microRNAs.

Saffron (Crocus sativus) versus duloxetine for treatment of patients with fibromyalgia: A randomized double-blind clinical trial.

OBJECTIVE: Saffron was found efficient and safe in treatment of neuropsychiatric disorders, in particular depression. We compared the efficacy of saffron with duloxetine in treatment of patients with fibromyalgia. MATERIALS AND METHODS: In this double-blind parallel-group clinical trial, outpatients with fibromyalgia were randomized to receive either saffron 15 mg or duloxetine 30 mg starting with 1 capsule per day in the first week followed by 2 capsules per day from week 2 until the end of week 8. Participants were men and women aged 18-60 years diagnosed with fibromyalgia based on the American College of Rheumatology 2010 criteria who also had a pain score≥40 based on visual analogue scale. Participants were excluded in case they had rheumatologic diseases, inflammatory/infectious/autoimmune arthritis, comorbid neuropsychiatric disorders except depressive disorders, pain due to traumatic injuries, drug history of duloxetine or saffron use, current use of psychoactive medications, recent use of muscle relaxants, steroids, opioid analgesics, benzodiazepines, anti-epileptics, or injective analgesics. Primary outcomes included differences in mean score changes from baseline to endpoint between the treatment arms for Hamilton Rating Scale for Depression, Fibromyalgia Impact Questionnaire, and Brief Pain Inventory. RESULTS: Socio-demographic characteristics and baseline scores were similarly distributed between the two treatment arms (2n=46). No significant difference was detected for any of the scales neither in terms of score changes from baseline to endpoint between the two treatment arms (Mean score changes: -4.26 to 2.37; p-values: 0.182-0.900) nor in terms of timetreatment interactions (p-values: 0.209-0.964). CONCLUSIONS: Saffron and duloxetine demonstrated comparable efficacy in treatment of fibromyalgia symptoms.

Prevalence of musculoskeletal disorders in southeastern Iran: a WHO-ILAR COPCORD study (stage 1, urban study).

OBJECTIVE: The purpose of this study was to determine the prevalence of musculoskeletal complaints and rheumatic diseases in southeast of Iran. METHODS: Subjects were selected based on a cluster sampling from 20 districts of urban areas in Zahedan, Iran. Subjects 15 years old and over were randomly selected and interviewed by trained interviewers in their houses. The Community Oriented Program for the Control of Rheumatic Disease (COPCORD) and Core Questionnaire (CCQ) were used in this study. The people with musculoskeletal complaints (pain, stiffness and swelling) were examined by the rheumatologist. Laboratory tests and radiographic exams were carried out when necessary to further categorize diagnoses. RESULTS: Data were collected from October 10, 2008 to September 15, 2009. Two thousand and one hundred subjects including 921 (43.9%) males and 1179 (56.1%) females were interviewed. The average age of the population was 33.1 ± 14.7 years. The prevalence of complaints within the past 7 days prior to the interview was 54.13%. The most common sites of complaint were as follows: knee (30.59%), dorsolumbar (28.83%), shoulder (22.26%) and neck (17.07%). The most common rheumatic diseases were osteoarthritis and low back pain with the prevalence of 18.66% and 17.71%, respectively. Finally, the prevalence of rheumatoid arthritis was 0.98%. CONCLUSION: Musculoskeletal complaints are highly common in southeast Iran. Knee and low back pain were the most common sites of complaints. The most frequent diagnosed diseases were osteoarthritis of knee followed by low back pain and soft tissue rheumatism. Rheumatoid arthritis was the most prevalent inflammatory disease.

Evaluation of depression in patients with cancer in South of iran (zahedan).

BACKGROUND: The symptoms related to depression in patients with cancer are amajor problem and could influence the treatment and survival of patients. This disorder is varied in different populations and in different studies. METHODS: We evaluated the prevalence of depression with Beck Depression Inventory (BDI) scale in 400 patients with cancer. This measurement was after the diagnosis of malignancy and before chemotherapy or radiotherapy. RESULTS: The mean age of patients was 45 ±8.5 years, and female to male ratio was 45/55. The prevalence of depression was 24.8 % and 28% in males and females. All patients with depression had mild to moderate depression. Prevalence of depression was significantly higher in younger cases (P<0.0001). According to the site of malignancy, prevalence of depression was significantly highest in patients with breast cancer, following metastatic of unknown origin and gastrointestinal cancer and the lowest prevalence was observed in patients with hematologic malignancy (p <0.0001). Also, we observed a significant higherprevalence of depression in single versus married patients (p <0.0001), in patients with higher education (p <0.0001) and patients who had knowledge about their disease in comparison with those who had no knowledge (p <0.0001). CONCLUSION: The prevalence of depression and its severity in cancer patients in South east of Iran was lower than other studies and it seems that this situation may be related to high religious beliefs in this region, high prevalence of illiteracy and lack of knowledge about their underlying disease.

Comparison of adenosine deaminase levels in serum and synovial fluid between patients with rheumatoid arthritis and osteoarthritis.

OBJECTIVES: Adenosine deaminase (ADA) is an enzyme being involved in purine metabolism and plays a significant role in the immune system. The aim of this study was to investigate the use of adenosine deaminase levels in differentiating between rheumatoid arthritis and osteoarthritis. MATERIAL AND METHODS: Thirty patients with rheumatoid arthritis and 30 osteoarthritis patients enrolled the study. They were matched in sex and age. Using the ROC curve, we determined the optimal serum and synovial cutoff for rheumatoid effusion. RESULTS: The results showed a statistically significant difference between ADA levels in joint effusion and serum of patients with rheumatoid arthritis and osteoarthritis (p<0.001). Synovial fluid cutoff value for diagnosing rheumatoid arthritis was 20 with a sensitivity of 90% and specificity of 80% and the serum cutoff value was 15 with a sensitivity of 93% and specificity of 53.3%. Area under ROC curve for synovial ADA, ESR and CRP co-linearity was 99%. CONCLUSION: We concluded that synovial total ADA assay can be a sensitive and specific test, being suitable for rapid diagnosis of rheumatoid effusions.

Prevalence of depression and depressive symptoms in patients with systemic lupus erythematosus: Iranian experience.

Psychiatric disorders including depression represent clinical manifestation of systemic lupus erythematosus (SLE). Recognition of depression in SLE patients is of utmost importance since it is treatable and can be of fatal consequences if unrecognized. This study was conducted to determine the prevalence of depression and depressive symptoms in SLE patients in terms of age, gender, disease duration and severity, and duration of steroid treatment in SLE patients. Eighty-five SLE patients (77 women, 8 men) with verified SLE diagnosis completed Beck's depression inventory, a self-reported measure of depression. Clinical data on disease and treatment were obtained from patient files. In total, 60% of patients achieved scores indicating depression. The most common depressive symptoms in participants were fatigue and weakness (88.2%), irritability (82.3%), sadness (77.6%), and somatic preoccupation (76.4%), while the least common symptoms were weight loss (34.1%), low level of energy (28.2%), and suicide ideation (10.5%). There was a significant difference between the disease activity and the severity of depression (P = 0.0001). Our findings show higher prevalence of depression in our sample in comparison with previous studies, suggesting that the prevalence of depression varies across different populations. Severity of depression increases with more severe disease course.

Predictors of initiation, continuation and transition of drug use in south-eastern Iran.

OBJECTIVES: To identify factors associated with the initiation continuation, transition and cessation of substance abuse in Zahedan, Iran. METHODS: The retrospective study reviewed the profile of 536 addicts admitted to both public and private outpatient treatment centres in the study area. For each individual, data were collected on sociodemographic characteristics, initiation and patterns of drug abuse and any changes in the patterns. To analyze the data, Kruskal-Wallis, Chi-square, Log-rank test, Logistic regression and Cox proportional hazards models were used. RESULTS: The median age of the first drug abuse was 20 (95% CI: 19.7 - 20.3) years with significant heterogeneity by gender and marital status (p < 0.001). The age of the first drug use and maritaI status were significant factors for the continuation of drug use (p < 0.001). The study also indicated that male gender, single life, low level of education, early onset of substance use and type of first used drug act as facilitators for transition to new drugs (p < 0.05). Besides, the present study revealed the significant effect of marital status, education and type of first used drug on personal decisions towards drug use cessation (p < 0.05). CONCLUSION: A number of predictive factors of substance abuse identified in the study are of utmost important for any preventive effort.