Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine with functions in nerve cell growth, differentiation, and apoptosis. There are several studies showing that a TNF-alpha--G308A promoter polymorphism, which possibly affects TNF-alpha transcription, is associated with schizophrenia, although negative results also exist. Our aim was to investigate the relationship between the TNF-alpha --G308A promoter polymorphism, the risk of schizophrenia, and the age of onset of schizophrenia, and the TNF-alpha -G308A polymorphism was therefore studied in 149 southern Finnish patients with a DSM-IV diagnosis of schizophrenia and in 393 healthy controls. The allele and genotype frequencies did not differ significantly between the patient and control groups (P=0.10 and 0.12, respectively), but the frequency of G/G homozygotes was statistically significantly higher in male patients than in male controls (chi(2)=5.03, d.f.=1, P=0.025) with an odds ratio of 2.00 (95% confidence interval: 1.08--3.70). No such difference was seen in female patients (P=0.79) or in the whole study group (P=0.064). The age of onset of schizophrenia did not differ significantly between the different TNF-alpha genotypes (ANOVA: F=0.45, P=0.64). In conclusion, we did not find a clear association between the TNF-alpha --G308A polymorphism and schizophrenia in the whole study group. However, TNF-alpha --G308A G/G homozygosity was modestly associated with schizophrenia in male patients.
"Although most of these genetic findings are not significant in genome-wide comparisons, they are consistent with studies that found altered levels of these cytokines in brain and plasma of schizophrenia patients (Table 1). For example, two studies have found that the high IL-10-producing haplotype is more frequent in schizophrenia patients (Bocchio Chiavetto et al., 2002; Ozbey et al., 2009) and similar findings have been reported for the TNFA gene (Boin et al., 2001; Hanninen et al., 2005). The above genes may also represent a link between genetic and environmental risk factors (Fig. 1), such as the association reported between polymorphisms in IL-18 pathway genes and susceptibility to herpes simplex virus (HSV) 1 (Shirts et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is a heterogeneous psychiatric disorder with a broad spectrum of clinical and biological manifestations. Due to the lack of objective tests, the accurate diagnosis and selection of effective treatments for schizophrenia remains challenging. Numerous technologies have been employed in search of schizophrenia biomarkers. These studies have suggested that neuroinflammatory processes may play a role in schizophrenia pathogenesis, at least in a subgroup of patients. The evidence indicates alterations in both pro- and anti-inflammatory molecules in the central nervous system, which have also been found in peripheral tissues and may correlate with schizophrenia symptoms. In line with these findings, certain immunomodulatory interventions have shown beneficial effects on psychotic symptoms in schizophrenia patients, in particular those with distinct immune signatures. In this review, we evaluate these findings and their potential for more targeted drug interventions and the development of companion diagnostics. Although currently no validated markers exist for schizophrenia patient stratification or the prediction of treatment efficacy, we propose that utilisation of inflammatory markers for diagnostic and theranostic purposes may lead to novel therapeutic approaches and deliver more effective care for schizophrenia patients.
Schizophrenia Research 08/2014; DOI:10.1016/j.schres.2014.07.025 · 3.92 Impact Factor
"and was reported to be associated with schizophrenia (Schwab et al., 2000); the TNFA –238 (G/A) and –308 (G/A) polymorphisms are involved in the regulation of TNF-α activation, by influencing TNF-α transcription, thus being involved directly in the production of TNF-α (Kaluza et al., 2000;Wilson et al., 1994). According to the association of the TNFA polymorphism and schizophrenia, a correlation has been reported in literatures, with conflicting results (Boin et al., 2001;Czerski et al., 2008;Duan et al., 2004;Handoko et al., 2003;Hanninen et al., 2005;Hashimoto et al., 2004;Kampman et al., 2005;Meira-Lima et al., 2003;Morar et al., 2007;Pae et al., 2003;Riedel et al., 2002;Saviouk et al., 2005;Schwab et al., 2003;Shirts et al., 2006;Tan et al., 2003;Tsai et al., 2003;Watanabe et al., 2007;Zai et al., 2006), although a recent meta-analyses including 2512 cases and 3223 controls showed that the AA genotype was weakly associated with schizophrenia susceptibility in Caucasoids (Odd Ratio OR=1.65, 95% CI=1.00-2.71 Z=1.98 p=0.05) (Sacchetti et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: Summary This study investigated the tumor necrosis factor-α gene (TNFA; -238 G/A and -308 G/A polymorphisms) on the development of schizophrenia, as well as the interaction of the two polymorphisms in relation to symptomatology, family history, onset age and antipsychotic treatment response. Genomic DNA analyses with polymerase chain reaction (PCR) were used for the genotyping. One hundred and fifty-two (152) patients with schizophrenia and 152 normal controls participated in the study. Any associations between the individual polymorphism and schizophrenia were not found. However, marginal association between subjects with TNFA -238 A allele (genotype AA plus AG) and presence of family history was found (p=0.023). No significant interaction effects between TNFA -238 and -308 polymorphisms either on the development of schizophrenia or on clinical variables such as antipsychotics treatment response and psychopathology were found, although a significant interaction effect for subjects carrying TNFA -238 AG and -308 AA genotypes on a positive family history was observed (p=0.017). These results suggest that the interaction effects between TNFA -238 and -308 polymorphisms gives no significant contribution to the susceptibility to schizophrenia, and is not associated with clinical variables, antipsychotic treatment response and psychopathological features, except for family history of disease, at least in Korean population.
"Interestingly, this allele has been associated with an increased transcription activity in vivo (Jeong et al., 2004). However, successive case–control and family-based replication studies in ethnically diVerent populations have yielded conXicting results (Duan et al., 2004; Handoko et al., 2003; Hanninen et al., 2005; Hashimoto et al., 2004; Kampman et al., 2005; Meira-Lima et al., 2003; Pae et al., 2003; Riedel et al., 2002; Saviouk et al., 2005; Schwab et al., 2003; Shirts et al., 2006; Tan et al., 2003; Tsai et al., 2003). The grounds for the frequent lack of reproducibility in psychiatric genetics can be multifaceted and generally could be ascribed to inadequate sample sizes, genotyping errors and sample stratiWcations, ethnically diVerent genetic backgrounds and gender diVerences, together with the diYculty in deWning phenotype (Craddock et al., 2006; Kavelaars and Heijnen, 2006; Ioannidis et al., 2001). "
[Show abstract][Hide abstract] ABSTRACT: Research on -G308A functional polymorphism in the tumor necrosis factor alpha (TNFalpha) gene as a susceptibility factor for schizophrenia has provided contrasting results in different populations. Therefore we conducted a meta-analysis of the published case-control association studies and a replication study in a large sample. Meta-analyses (total sample: 2512 cases versus 3223 controls) showed that the AA genotype was weakly associated with schizophrenia susceptibility in Caucasoids (Odd Ratio OR=1.65, 95% CI=1.00-2.71 Z=1.98 p=0.05). The replication case-control association study (323 DSM-IV-TR schizophrenia patients and 346 controls) showed that the A allele conferred an increased susceptibility for schizophrenia only in males (OR=1.73, 95% CI=1.07-2.79, p=0.025), and the association became more specific when only patients of the paranoid subtype were compared to the controls (relative risk ratio=3.09, 95% CI=1.28-7.47, p=0.012). The presence of the A allele was also associated with a later age at onset of schizophrenia in the whole sample (F(1,291)=7.094, p=0.008). Our results confirm that TNFalpha A allele could have an effect on vulnerability to schizophrenia but further studies revaluating the role of gender and diagnostic subtypes are necessary to confirm these findings.
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