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Schizophrenia is complex and clinically heterogeneous psychiatric disorder that has an evidenced genetic basis. Several reports indicate a possible role of the activation of the immune system in the pathogenesis of schizophrenia. CD28 is a molecule expressed on T-cells that provides the major co-stimulatory signal required for activation of immune response. For many years now, it has been strongly advocated that biological underpinnings of schizophrenia should be investigated with respect to subpopulations of subjects defined by homogenous symptomatology.
To investigate the association of polymorphism of the CD28 gene (T17int3C) with respect to schizophrenia symptomatology.
Material and methods
105 patients diagnosed with schizophrenia according to ICD-10 criteria and 380 controls were included in the study. The patients were diagnosed using the Operational Criteria for Psychotic Illness checklist (OPCRIT). Based on confirmatory factor analysis on OPCRIT items performed by Serretti et al. (2004), in our study we considered five factors of symptomatology (mania, positive symptoms, disorganization, depression and negative symptoms).
There was significant difference in distribution of genotypes between patients with schizophrenia with co-occurring manic symptoms and without co-occurring manic symptoms (respectively CC and/or TC: 23% vs. 47%, TT: 77% vs. 53%, p=0,040). There was also difference in distribution of genotypes between patients with schizophrenia with co-occurring depressive symptoms and without cooccurring depressive symptoms (respectively CC and/or TC: 24% vs. 47%, TT: 76% vs. 53%, p=0,043).
We have shown that CD28 gene polymorphism might increase risk for affective (depressive and/or manic) symptom dimension in schizophrenic patients.
Genetic factors that modulate the immune response have been implicated as risk factors both for schizophrenia as well as for cognitive impairments (endophenotypes of schizophrenia). Regulation of immune response is mediated by two related receptors: CD28 is a major co-stimulator, whereas CTLA-4 performs negative regulatory functions. Balance of immune response depends on the expression of these regulatory molecules due to their genes polymorphisms.
The study was carried out to investigate the association between polymorphisms of two genes: CTLA-4 (49A/G, −319C/T, CT60 A/G) and CD28 (+17C/T) and frontal lobe functions in patients with schizophrenia.
118 patients diagnosed with schizophrenia (ICD-10) and 352 controls were included in the study. Frontal lobe functioning was assessed by Trail Making Test (TMT) and Stroop Test (SCWT).
There was no significant difference in distribution of genotypes between patients and controls in the polymorphisms of CTLA-4 gene, but in polymorphism of CD28 gene (p = 0,0007). With respect to +17C/T CD28 gene polymorphism there was a trend level difference in performance on TMT: C allel carriers performed worse that T allel carriers (p = 0,054), suggesting weaker executive control function.
Our data support a role of CD28 +17 C/T gene polymorphisms for the predisposition to schizophrenia. Among patients the distribution of genotypes of CD28 gene polymorphism is similar to that found in patients with autoimmune disorders such as: early onset type 1 diabetes and Behçet's disease. Additionally, +17C/T CD28 gene polymorphism might be considered as a risk factor for cognitive impairment in schizophrenia.
Neuregulin-1 (NRG1) may be an important factor in pathogenesis of schizophrenia due to its role in neurodevelopmental processes: myelination, neurotransmitter receptor expression and synaptic plasticity. NRG1 has been also implied to play role in cognitive impairments, which are considered to be endophenotypes of schizophrenia, i.e. subclinical, heritable and independent of clinical state traits associated with genetic susceptibility. Surprisingly, a recent meta-analysis (Dickinson, 2007) demonstrated that reliable and easy to administer Digit Symbol Coding Task (DSCT) discriminate people with schizophrenia from comparison individuals better than the more widely studied neuropsychological instruments.
The study was carried out to investigate the association of a polymorphisms of the NRG1 gene (rs62510682) and schizophrenia with respect to performance on DSCT.
Material and methods
We included 103 patients diagnosed with schizophrenia according to ICD-10 criteria and 578 controls in our study. The patients were evaluated for lifetime psychotic symptomatology using the Operational Criteria for Psychotic Illness (OPCRIT) checklist. DSCT was administered to 80 patients.
The polymorphisms were in HWE both in the cases’ and controls’ groups. In single marker analysis, we did not find an association for the SNP tested. However; we have found that T allel carriers (TT and/or GT genotype) performed worse than G allel carriers (p=0.4) suggesting weaker cognitive processing efficiency.
Our data do not support the role of the NRG1 gene polymorphism (rs62510682) in the predisposition to schizophrenia; however, the studied SNP might be considered to be a risk factor for cognitive impairment in schizophrenia.
Neuregulin-1 (NRG1) and DISC1 may be important factors in pathogenesis of schizophrenia due to their role in neurodevelopmental processes. NRG1 and DISC1 link directly into a common pathway mediated by Erb receptors and P13K/AKT1 signaling and have been implied to play role in cognitive impairments. Digit Symbol Coding Task (DSCT) from WAIS-R is a sensitive measure for cognitive decline in schizophrenia as well as it indexes poor prognosis and functional disability in schizophrenia.
The study was carried out to investigate the association of a polymorphisms of the NRG1 gene (rs62510682) as well as of DISC1 gene (rs1538979) and schizophrenia with respect to performance on DSCT.
Material and methods:
We included 103 patients diagnosed with schizophrenia according to ICD-10 criteria and 578 controls. In addition to unstructured interviews and review of medical records, the patients were evaluated for lifetime psychotic symptomatology using OPCRIT checklist. DCSTR was administered to 80 patients.
The polymorphisms were in HWE for healthy controls and schizophrenia patients. In single marker analysis, we did not find an association for the SNPs tested. However; with respect to DCST we found that with respect to NRG1 gene T allel carriers performed worse than G allel carriers (p<0.5) and with respect to DISC1 gene patients with TC genotype performed worse than with CC genotype (p<0.05).
Our data do not support the role of NRG1 or DISC gene polymorphisms in the predisposition to schizophrenia; however, they might be considered as risk factors for the cognitive decline in schizophrenia.
Schizophrenia is a chronic severe psychiatric disorder with multiple environmental and genetic determinants. Several reports indicate the possible role of immune system dysregulation in the pathogenesis of schizophrenia. An accumulating body of evidence indicates an association of schizophrenia and its psychopathology with altered cytokine production. The variation of the level of cytokines might be partly due to their functional gene polymorphism.
The study was carried out to investigate the association of schizophrenia with the following cytokine polymorphisms: IL-2 (-330T/G), IL-6 (-174G/C), IFN-gamma (+874 T/A), TGF-beta (+869 T/C and +915 G/C).
Material and methods
We included 130 patients diagnosed with schizophrenia and 184 controls in our study. The patients were evaluated for lifetime psychotic symptomatology using the Operational Criteria for Psychotic Illness (OPCRIT) checklist. The patients having history of traumatic brain injury, neurologic disorders, substance abuse or immune related diseases were excluded from the study by detailed medical examination.
The polymorphisms were in HWE both in the cases’ and controls’ groups. In single marker analysis, we did not find an association for the tested polymorphisms.
Our data do not support the role of IL-2, IL-6, IFN-gamma and TGF-beta gene polymorphisms in the predisposition to schizophrenia in the Polish population.
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