Involvement of CXCL10 rs4256246, CXCR4 rs2228014, CCR2 rs1799864 and CXCL16 rs2277680 in the Predisposition to Schizophrenia.

Chemokine ligands and their receptors have acquired less attention than pro- and anti-inflammatory cytokines in schizophrenia (SCZ). Thus, we aimed to examine the impact of functional polymorphisms of the chemokine genes CXCL10, CXCL16, CXCR4, and CCR2 in the development of SCZ. Using PCR-RFLP, we analyzed the selected polymorphisms in a Tunisian cohort composed of 200 patients with SCZ and 200 healthy controls. Our preliminary data suggest that the minor allele A of CXCL10 rs4256246 is significantly associated with likelihood of SCZ (PAdjusted = 0.00002) and more precisely to paranoid patients with late-onset SCZ (PAdjusted = 0.0007). However, the mutated allele T of CXCR4 rs2228014 showed a significant protective impact against SCZ (PAdjusted = 0.000007) and especially to male sex (PAdjusted = 0.000003). This effect persists among the undifferentiated patients with early-onset SCZ (PAdjusted = 0.002). Following the stratified analyses, CCR2 rs1799864 and CXCL16 rs2277680 were significantly correlated with the clinical symptoms among disorganized patients. As regards haplotype analysis, we noted that GATG haplotype was associated with protection against SCZ (PAdjusted = 0.0087) but the AGCG haplotype was correlated with susceptibility to this disease (PAdjusted = 0.014). Our preliminary results suggested that CXCL10 rs4256246 enhanced susceptibility to SCZ, while CXCR4 rs2228014 seemed to be protective factor. Furthermore, we identified a substantial correlation between CCR2 rs1799864 and CXCL16 rs2277680 with the clinical signs of the disorder. To validate these results and clarify the functional significance of the targeted polymorphisms in SCZ, more independent research is needed.

A new tool for genotoxic risk assessment: Reevaluation of the cytokinesis-block micronucleus assay using semi-automated scoring following telomere and centromere staining.

BACKGROUND: The cytokinesis-block micronucleus (CBMN) assay is an internationally recognized method for measuring DNA damage after exposure to genotoxic agents, as well as a biomarker for DNA repair and chromosomal instability. The high baseline level of micronuclei (MN) in the healthy population has limited the sensitivity and application of the CBMN assay for the follow-up of exposed populations. We reevaluated the sensitivity of the CBNM assay using semi-automated MN scoring following telomere and centromere (TC) staining after in vitro exposure to genotoxic agents (mitomycin or radiation) or aneugenic agents (vinblastine). MATERIALS AND METHODS: Blood samples from 12 healthy donors were exposed to 137Cs at seven doses from 0.1-4 Gy and cultured for 72 h. Cytochalasin B was added at 46 h of culture. The exposure of chemical agents (mitomycin or vinblastine) was performed after 48 h of culture for 3 h. Cytochalasin B was added after treatment and slides were prepared 24 h after. MN was semi-automatically scored following TC staining. Nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) were assessed in a human cell line after TC staining. RESULTS: The introduction TC staining to the scoring of MN not only renders MN scoring more efficient and robust, but also permits discrimination between exposure to clastogenic (MN with only telomere signals) and aneugenic agents (MN with both TC signals). The resulting improvement of MN detection led to an increase in the sensitivity of the CBMN assay following low-dose radiation exposure (0.3 versus 0.1 Gy). Hyperradiosensitivity phenomenon was observed after low dose exposure. A dose-response curve was obtained for up to 4 Gy. In addition, TC staining permits assessment of the nature of NPBs and NBUDs as biomarkers for genotoxicity and chromosomal instability. CONCLUSION: These approaches can be potentially used to follow-up populations exposed to genotoxic agents and assess cancer risk.

Effects of glutathione S-transferase M1 andT1 deletions on bipolar disorder risk among a Tunisian population.

Glutathione S-transferases (GSTs) enzymes are involved in the detoxification of several endogenous and exogenous substances. In this study, we evaluated the effects of two glutathione S-transferase polymorphisms, (GSTM1 and GSTT1) on bipolar disorder (BPD) risk susceptibility in a Tunisian population. These polymorphisms were analyzed in 229 healthy subjects and 109 patients with BPD, using a polymerase chain reaction. Statistical analysis was performed using SPSS 18.0. The relative associations between the GSTs genotypes and BPD were assessed by calculating odds ratios (ORs) and 95% confidence intervals (CLs). The study results demonstrated that individuals with GSTM1 [OR=1.51, 95% CI: 0.93-2.45, p=0.081] or GSTT1 [OR=1.65, 95% CI: 0.95-2.88, p=0.060] were not associated with the risk of BPD, whereas a significant association was found between individuals with both GSTM1/T1 null genotype and BPD risk [OR=2.96, 95% CI (1.26-7.03), p=0.005]. These genotyping finding revealed that the absence of both GSTM1 and GSTT1 activity could be a contributor factor for the development of BPD.

IFNGR2 genetic polymorphism associated with sex-specific paranoid schizophrenia risk.

BACKGROUND: Considering current scientific evidence about the significant role of chronic low grade inflammation in the physiopathology of schizophrenia, it has been hypothesized that changes in pro-inflammatory cytokines such as interferon gamma may have a significant role in the predisposition to schizophrenia. AIM: This study focuses on identifying whether the functional polymorphism of interferon gamma receptor 2 (IFNGR2) is a risk factor for the development of schizophrenia. METHODS: This study was conducted by the RFLP-PCR on a Tunisian population composed of 225 patients with different sub-types of schizophrenia and 166 controls. RESULTS: The IFNGR2 (Q64R) polymorphism analysis showed higher frequencies of minor homozygous genotype (RR) and allele (R) in all patients compared to controls (21.8% vs 10.2%; p = .006, OR = 2.54) and (44% vs 34.9%; p = .01; OR = 1.46), respectively. This correlation was confirmed only for males. This study also noted a significant increase of the mutated homozygous (RR) genotype and (R) allele frequencies of IFNGR2 in paranoid schizophrenics compared to controls (31.4% vs 10.2%; p = .001; OR = 3.34 and 47.2% vs 34.9%; p = .009; OR = 1.66, respectively). This increase remains significant after using binary logistic regression to eliminate confounding factors such as age and sex. Additionally, carriers of RR genotype have significant lower scores on the Scale of Assessment of Positive (SAPS) and negative (SANS) symptoms comparatively to the carrier of the QQ + QR genotypes, suggesting that the R recessive allele carriers could have milder symptoms. CONCLUSION: The IFNGR2Q64R polymorphism is correlated with male sex and paranoid schizophrenia. It is suggested that a chronic neuroinflammation may predispose to the paranoid schizophrenia development in men.

C3 Polymorphism Influences Circulating Levels of C3, ASP and Lipids in Schizophrenic Patients.

Excessive activation of complement is associated with many diseases including schizophrenia. Investigation of C3 polymorphisms, circulating C3, cleavage product ASP/C3adesArg, and lipid metabolism. Cross-sectional analysis. C3 genotyping (CC vs GG for R102L) was performed on 434 Tunisian people consisting of 272 schizophrenic (SZ) patients and 162 control subjects. In a age- and gender-matched subgroups of the three genotypes (131 SZ and 112 NOR), plasma triglycerides, total cholesterol (C), LDL-C, HDL-C, ASP, and complement C3 were measured. C3 gene polymorphism influences BMI and plasma C3, ASP, triglyceride, total cholesterol, LDL-C and HDL-C among SZ patients (p < 0.05-0.0001), with increasing values demonstrated from CC (common form) to CG (heterozygote form) to GG (rare homozygote) forms. Significant correlations between plasma C3 and BMI, triglyceride, HDL-C and ASP (p < 0.05-0.0001) were observed, while ASP correlated with BMI and LDL-C (p = 0.005, p = 0.001, respectively) in SZ patients. Further, proportional conversion of C3 to ASP (%ASP/C3) also increased (p < 0.0001, GG>CG>CC). C3 polymorphisms and plasma C3, ASP and %ASP/C3 correlated with lipid parameters in this SZ population, suggesting that factors predisposing patients to schizophrenia are permissive for complement pathway activation and dyslipidemic influences.

Association of the Met-196-Arg variation of human tumor necrosis factor receptor 2 (TNFR2) with paranoid schizophrenia.

Research has provided strong evidence for oligodendrocyte and myelin-related genes dysfunction in schizophrenia. Several studies have suggested abnormalities in the expression of myelin-related genes including tumor necrosis factor receptor 2 (TNFR2) involved in the neurodegeneration and remyelination. In order to further assess the role of TNFR2 in schizophrenia, we examined a functional bi-allelic polymorphism associated with an impaired NF-KB signaling and cell survival. In the present case/control study, 220 patients with schizophrenia and 176 healthy controls were genotyped by RFLP-PCR for the T/G polymorphism at the position 676 in exon 6 of the TNFR2 gene. We found a trend towards over-representation of TNFR2 676G in the patients compared to the controls (p=0.19 and 0.09 respectively). Interestingly, when we evaluated the association between this genetic polymorphism and the clinical variables of schizophrenia, our findings indicated that the frequencies of the G/G genotype and the G allele were significantly higher in paranoid (p=0.014 and p=0.012 respectively) and adult-onset paranoid (p=0.004 and p=0.004 respectively) schizophrenia patient group compared to the controls. The potential association was confirmed by a logistic regression model only for development of the paranoid form of schizophrenia (p=0.022) indicating a substantially increased risk for paranoid schizophrenia with inheritance of the TNFR2(G) allele. In conclusion, this polymorphism in TNFR2 or a gene in proximity seems to be associated specifically with paranoid schizophrenia, at least in the Tunisian population. A replication of our findings in other and larger populations could be of particular importance to establish TNFR2 as one of the susceptibility genes of paranoid schizophrenia.