Association of blood levels of C-reactive protein with clinical phenotypes in Arab schizophrenic patients

Schizophrenia may be associated with inflammatory reactions and C-reactive protein (CRP) is a nonspecific serum protein marker for persisting inflammatory states. This study aimed to assess concentrations of high sensitivity CRP (hsCRP) in schizophrenic Arab patients and evaluate the relationships of hsCRP levels with aspects of clinical phenotypes of the disease. Two age-matched groups of subjects were studied: (1) healthy controls, HC, n = 165; (2) patients with schizophrenia, SZ: n = 207. Each subject was evaluated with a standard questionnaire for age at disease onset, family history, disease severity and outcome. Serum hsCRP levels were measured by immunoassay. The two groups of subjects were similar in age, ethnic composition and socioeconomic status. Those with SZ had significantly greater serum concentrations of hsCRP. There were significant associations between hsCRP and (i) age in both groups; (ii) body mass index (BMI) in HC but not in SZ. In the latter, hsCRP levels were: (a) marginally higher in women with later age of disease onset; (ii) highest with remission and with catatonic features; and (iii) lower with family history of psychosis. The study concludes that serum levels of hsCRP are increased in clinically stable Arab patients with schizophrenia and appear related to the disorder's clinical expression. It is suggested that there may be an inflammatory component to schizophrenia which is associated with aspects of its clinical phenotype.     

Potential involvement of the interleukin-18 pathway in schizophrenia

ObjectiveAccumulating evidence implicates inflammatory cytokines in the development of psychiatric disorders, including schizophrenia (SZ). IL-18 is one of cytokines that plays a crucial role in immune response and neurodevelopment. We aimed to investigate potential genetic alterations of the cytokine system underpinning SZ.MethodsWe tested the association of genetic variants within the cytokine–cytokine receptor interaction (CCRI) pathway with SZ, using GWAS-derived data involving 768 adult SZ patients and 1348 controls, and replicated the association of IL18R1 rs1035130 with SZ in an independent sample of 1957 adult patients and 1509 controls. We compared expression levels of IL18, IL18R1 and IL18RAP in peripheral blood of a cohort of adolescent participants (<18 years), including 14 early-onset SZ patients and 13 healthy controls. Furthermore, we carried out a cis-eQTL (expression Quantitative Trait Loci) and a cis-mQTL (Methylation Quantitative Trait Loci) analysis for IL18R1 rs1035130.ResultsIn the discovery stage, we detected association signals within two IL18 pathway genes, IL18R1 and IL18RAP, with the most significant marker being IL18R1 rs1035130 (P = 1.84E-7, OR = 0.70). In the validation stage, we found rs1035130 was associated with SZ (P = 0.028, OR = 0.89). Expressions of IL18 and IL18R1 were altered in blood of SZ patients compared with 13 controls. Furthermore, cis-QTL analyses indicated that rs1035130 was associated with an eQTL and 5 mQTLs.ConclusionOur findings suggest the alteration of IL18 pathway may contribute to the psychopathology of SZ.     

Lack of association to a NRG1 missense polymorphism in schizophrenia or bipolar disorder in a Costa Rican population

A missense polymorphism in the NRG1 gene, Val>Leu in exon 11, was reported to increase the risk of schizophrenia in selected families from the Central Valley region of Costa Rica (CVCR). The present study investigated the relationship between three NRG1 genetic variants, rs6994992, rs3924999, and Val>Leu missense polymorphism in exon 11, in cases and selected controls from an isolated population from the CVCR. Isolated populations can have less genetic heterogeneity and increase power to detect risk variants in candidate genes. Subjects with bipolar disorder (BD, n=358), schizophrenia (SZ, n=273), or unrelated controls (CO, n=479) were genotyped for three NRG1 variants. The NRG1 promoter polymorphism (rs6994992) was related to altered expression of NRG1 Type IV in other studies. The expression of NRG1 type IV in the dorsolateral prefrontal cortex (DLPFC) and the effect of the rs6994992 genotype on expression were explored in a postmortem cohort of BD, SZ, major depressive disorder (MDD) cases, and controls. The missense polymorphism Val>Leu in exon 11 was not significantly associated with schizophrenia as previously reported in a family sample from this population, the minor allele frequency is 4%, thus our sample size is not large enough to detect an association. We observed however an association of rs6994992 with NRG1 type IV expression in DLPFC and a significantly decreased expression in MDD compared to controls. The present results while negative do not rule out a genetic association of these SNPs with BD and SZ in CVCR, perhaps due to small risk effects that we were unable to detect and potential intergenic epistasis. The previous genetic relationship between expression of a putative brain-specific isoform of NRG1 type IV and SNP variation was replicated in postmortem samples in our preliminary study.     

C-reactive protein serum level in drug-free male Egyptian patients with schizophrenia

Despite the growing research interest in the role of immunological markers in schizophrenia, few studies, with conflicting results, have focused on the association between high sensitivity C-reactive protein (hs-CRP) levels and clinical characteristics in schizophrenia. In this cross-sectional case-control study, a sample of 200 antipsychotic-free male Egyptian schizophrenia patients was assessed by the Positive and Negative Syndrome Scale (PANSS) and compared with 200 healthy controls as regards serum hs-CRP level using an immunoturbidimetric method. CRP level for patients (geometric mean = 3.3 mg/L) was significantly (P = 0.000) higher than that for controls (geometric mean = 1.4 mg/L). PANSS scores and patients' data, which significantly correlated with serum hs-CRP level, were entered into a stepwise multiple regression analysis. Results of this analysis showed that PANSS negative symptom score was second only to the waist circumference, with which they explained 54.7 % of the variation in serum hs-CRP. Comparable results were obtained when patients, controls and the relevant confounders were included in one multivariate analysis. We concluded that in Egyptian men, waist circumference and schizophrenia diagnosis are strong predictors of raised CRP level independent of a number of potentially confounding variables. In antipsychotic-free patients, CRP level is higher than in healthy controls and is positively correlated with the severity of the psychopathology as measured by PANSS. This relationship is especially notable in negative, but not positive symptoms.     

C-反应蛋白与精神分裂症的关系研究进展

精神分裂症与免疫或炎症反应相关已在学界达成共识。C-反应蛋白(CRP)作为炎症免疫学标志物之一,是否具有作为精神分裂症免疫学标志物的潜力,已引起了研究者的关注。本文目的是通过回顾近年来国内外关于CRP与精神分裂症的关系研究,总结目前该领域研究进展,旨在为未来这一方向的研究提供参考。     

Association Between NOS1 Gene Polymorphisms and Schizophrenia in Asian and Caucasian Populations: A Meta-Analysis

Schizophrenia is a complex psychiatric disorder characterized by memory impairments with delusions and hallucinations. Several investigations have focused on determining the association between NOS1 (nitric oxide synthase-1) polymorphisms and risk of schizophrenia (SZ). However, the association of rs2682826, rs3782206, rs499776, rs3782219, rs41279104, rs3782221, rs1879417, rs4767540, rs561712, and rs6490121 polymorphisms with schizophrenia remains inconclusive. We performed a systematic meta-analysis for each polymorphism to determine its association with SZ by calculating their pooled odds ratio and 95% confidence intervals. The heterogeneity between studies was evaluated using Cochran’s Q test to adopt random effects or fixed effects model. Based on our analysis, the rs3782206 polymorphism showed a strongest association with schizophrenia in allelic OR 1.15 (95% CI [1.05–1.25]), homozygote OR 1.35 (95% CI [1.09–1.66]), dominant OR 1.16 (95% CI [1.04–1.29]), and recessive OR 1.29 (95% CI [1.05–1.58]) models in Asian population. Similarly, in Caucasian population, the rs499776 polymorphism attributes risk association in homozygote OR 0.70 (95% CI [0.50–0.98]), dominant OR 3.57 (95% CI [2.34–5.27]), and recessive models OR 0.68 (95% CI [0.50–0.93]) with schizophrenia. Further, the sensitivity analysis was carried out based on leave-one-out method to confirm the reliability of the analysis. Overall, our meta-analysis demonstrates the significance of NOS1 genetic variants that are functionally associated with cognitive and neuropsychiatric symptoms of schizophrenia.     

Association study of RELN polymorphisms with schizophrenia in Han Chinese population

Schizophrenia (SZ) is a common and complex psychiatric disorder with a strong genetic component. Previous research suggests that mutations altering genes in neurodevelopmental pathways contribute to SZ. Reelin gene (RELN) maps to chromosome 7q22.1, the encoded protein plays a pivotal role in guiding neuronal migration, lamination and connection during embryonic brain development. Several reports had indicated that reduced RELN expression is associated with human mental illnesses such as SZ, mood disorders and autism. In this study, case-control association analyses were performed in the Han Chinese population to determine if the RELN gene is a susceptibility gene for SZ. Thirty-seven single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 control subjects. A significant association was found between rs12705169 and SZ (p = 0.001). Moreover, the haplotypes constructed from five SNPs showed significant differences between cases and controls (p = 0.041). When subjects were divided by gender, rs12705169 remained significant difference only in females (OR = 0.24, 95%CI = 0.14-0.40 for CC and OR = 0.40, 95%CI = 0.27-0.58 for AC), both in the allele and genotype (p = 0.0001 for both). This study describes a positive association between RELN and SZ in the Han Chinese population, and provides genetic evidence to support the gender difference of SZ.     

Cross-diagnostic comparison of visual processing in bipolar disorder and schizophrenia

Patients with Schizophrenia (SZ) show deficits across various stages of visual information processing. Whether patients with Bipolar Disorder (BD) exhibit these deficits is unclear. In this study, we conducted a detailed comparison of specific stages of early visual perception in BD and SZ. Forty-three BD patients, 43 SZ patients, and 51 matched healthy control subjects (HC) were administered three visual processing paradigms emphasizing: 1) an early stage of object formation (location backward masking), 2) a middle stage of object substitution (four-dot backward masking), and 3) a later stage at the perception–attention interface (rapid serial visual processing (RSVP) task eliciting the attentional blink). SZ performed significantly worse than BD and HC on location and four-dot masking. BD did not significantly differ from HC on either masking task. Both patient groups performed significantly worse than HC on the RSVP task; unlike SZ, BD did not show a significant attentional blink effect compared to HC. Our results indicate that BD patients were intact at the early and middle stages of visual processing (object formation and substitution) but intermediate between the SZ and HC groups at a later processing stage involving perceptual and attentional processes (RSVP task). These findings suggest that SZ is characterized by a diffuse pathophysiology affecting all stages of visual processing whereas in BD disruption is only at the latest stage involving higher order attentional functions.     

Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia

Several lines of evidence have implicated the catechol-O-methyltransferase (COMT) gene as a candidate for schizophrenia (SZ) susceptibility, not only because it encodes a key dopamine catabolic enzyme but also because it maps to the velocardiofacial syndrome region of chromosome 22q11 which has long been associated with SZ predisposition. The interest in COMT as a candidate SZ risk factor has led to numerous case-control and family-based studies, with the majority placing emphasis on examining a functional Val/Met polymorphism within this enzyme. Unfortunately, these studies have continually produced conflicting results. To assess the genetic contribution of other COMT variants to SZ susceptibility, we investigated three single-nucleotide polymorphisms (SNPs) (rs737865, rs4633, rs165599) in addition to the Val/Met variant (rs4680) in a highly selected sample of Australian Caucasian families containing 107 patients with SZ. The Val/Met and rs4633 variants showed nominally significant associations with SZ (P<0.05), although neither of the individual SNPs remained significant after adjusting for multiple testing (most significant P=0.1174). However, haplotype analyses showed strong evidence of an association; the most significant being the three-marker haplotype rs737865-rs4680-rs165599 (global P=0.0022), which spans more than 26 kb. Importantly, conditional analyses indicated the presence of two separate and interacting effects within this haplotype, irrespective of gender. In addition, our results indicate the Val/Met polymorphism is not disease-causing and is simply in strong linkage disequilibrium with a causative effect, which interacts with another as yet unidentified variant approximately 20 kb away. These results may help explain the inconsistent results reported on the Val/Met polymorphism and have important implications for future investigations into the role of COMT in SZ susceptibility.     

Evaluation of Six SNPs of MicroRNA Machinery Genes and Risk of Schizophrenia

MicroRNAs (miRNAs) are small regulatory RNAs that modulate the expression of approximately half of all human genes. Small changes in miRNA expression have been associated with several psychiatric and neurological disorders, but whether the polymorphisms in genes involved in the processing of miRNAs into maturity influence the susceptibility of a person to schizophrenia (SZ) has not yet been elucidated. In this study, we investigated the association between SZ risk and single-nucleotide polymorphisms (SNPs) in microRNA machinery genes. We assessed the associations between SZ as a risk and six potentially functional SNPs from five miRNA processing genes (DROSHA, DGCR8, DICER, AGO1, and GEMIN4) in a case-control study of 256 Chinese SZ patients and 252 frequency-matched (age, gender, and ethnicity) controls. All the SNPs (rs10719, rs3757, rs3742330, rs636832, rs7813, and rs3744741) were genotyped by high resolution melting method. We found that two SNPs in the DGCR8 and DICER gene were significantly associated with the altered SZ risk. The genotype or allele frequency of rs3742330 in DICER was significantly different in patients and controls. Moreover, the recessive model of rs3757 in DGCR8 (AA vs. GA/GG) exhibited a significantly increased risk with an odds ratio (OR) of 3.73 [95 % confidence interval (CI), 1.03–13.52, P?=?0.032]; the dominant model of rs3742330 in DICER (AA vs. AG/GG) exhibited a significantly increased risk with OR of 1.49 (95 % CI, 1.04–2.13; P?=?0.028). Other SNPs and the haplotype of GEMIN4 (rs3744741 and rs7813) did not show any association with SZ. Our results suggested that the specific genetic variants in microRNA machinery genes may affect SZ susceptibility.     

Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population

The phosphodiesterase 4B (PDE4B) gene is located at 1p31, a susceptibility region for schizophrenia (SZ). Moreover, PDE4B interacts with DISC1, which is a known genetic risk factor for SZ. Recently, it was reported that the PDE4B gene is associated with SZ in Caucasian and African American populations. In this study, case-controlled association analyses were performed in the Japanese population to determine if the PDE4B gene is implicated in SZ. Thirteen single nucleotide polymorphisms (SNPs) were analyzed in 444 schizophrenic patients and 452 control subjects. Three SNPs (rs2180335, rs910694 and rs472952) were significantly associated with SZ after applying multiple test correction (p = 0.039, 0.004 and 0.028). In addition, a significant association was found between specific haplotypes (rs2180335 and rs910694) and SZ (permutation p = 0.001). Our result suggests that variations at the PDE4B locus may play a significant role in the etiology of SZ in the Japanese population.     

Positive association of the PDE4B (phosphodiesterase 4B) gene with schizophrenia in the Japanese population

The phosphodiesterase 4B (PDE4B) gene is located at 1p31, a susceptibility region for schizophrenia (SZ). Moreover, PDE4B interacts with DISC1, which is a known genetic risk factor for SZ. Recently, it was reported that the PDE4B gene is associated with SZ in Caucasian and African American populations. In this study, case-controlled association analyses were performed in the Japanese population to determine if the PDE4B gene is implicated in SZ. Thirteen single nucleotide polymorphisms (SNPs) were analyzed in 444 schizophrenic patients and 452 control subjects. Three SNPs (rs2180335, rs910694 and rs472952) were significantly associated with SZ after applying multiple test correction (p = 0.039, 0.004 and 0.028). In addition, a significant association was found between specific haplotypes (rs2180335 and rs910694) and SZ (permutation p = 0.001). Our result suggests that variations at the PDE4B locus may play a significant role in the etiology of SZ in the Japanese population.     

Elevated inflammatory markers in women with remitted major depressive disorder and the role of early life maltreatment

Major depressive disorder (MDD) has been linked to elevated inflammation markers. It remains unclear whether the elevation of C-reactive protein (CRP) and interleukin-6 (IL-6) levels are not only observable in acute MDD but also in patients after remission. MDD is a common sequela of early life maltreatment (ELM), which has also been associated with elevated inflammation markers. While the majority of studies investigated (acute) MDD and ELM as isolated predictors of inflammation, a few studies found inflammation levels to be more pronounced in patients with MDD that were exposed to ELM. This investigation included both ELM and MDD in one study and aimed at distinguishing between the effects of MDD in remission (rMDD) and ELM and investigating potential accumulative effects on the inflammatory markers CRP and IL-6 in a population of N = 126 women (n = 122 for CRP and n = 66 for IL-6). We further investigated how disorder characteristics (course and severity) and specific types of ELM affect levels of CRP and IL-6. We found that rMDD predicted levels of CRP and IL-6 and physical abuse predicted levels of CRP when considering both predictors simultaneously, while other types of ELM did not. A later onset of MDD and a shorter time interval since the last episode were associated with higher levels of IL-6. Our findings contribute to the existing literature on the association between MDD and inflammation, suggesting that elevated levels of inflammation markers may persist even after remission of MDD. Our findings on physical abuse as a specific predictor of CRP in the presence of rMDD suggest that different types of ELM could result in distinct inflammation profiles.     

Eye gaze perception in bipolar disorder: Self‐referential bias but intact perceptual sensitivity

Objectives

Deficits in social cognition predict poor functional outcome in severe mental illnesses such as schizophrenia and autism. However, research findings on social cognition in bipolar disorder (BD) are sparse and inconsistent. This study aimed to characterize a critical social cognitive process—eye gaze perception—and examine its functional correlates in BD to inform psychopathological mechanisms.

Methods

Thirty participants with BD, 37 healthy controls (HC), and 46 psychiatric controls with schizophrenia (SZ) completed an eye‐contact perception task. They viewed faces with varying gaze directions, head orientations, and emotion, and made eye‐contact judgments. Psychophysics methods were used to estimate perception thresholds and the slope of the perception curve, which were then compared between the groups and correlated with clinical and functional measures using Bayesian inference.

Results

Compared with HC, patients with BD over‐perceived eye contact when gaze direction was ambiguous, and this self‐referential bias was similar to that in SZ. Patients with BD had lower thresholds (i.e., needed weaker eye‐contact signal to start perceiving gaze as self‐directed) but a similar slope compared with HC. Regression analyses showed that steeper slope predicted better socio‐emotional functioning in HC and SZ, but not in BD.

Conclusions

The psychopathology of social dysfunction was fundamentally different between BD and SZ in this modest sample. Eye gaze perception in BD was characterized by a self‐referential bias but preserved perceptual sensitivity, the latter of which distinguished BD from SZ. The relationship between gaze perception and broader socio‐emotional functioning in SZ and HC was absent in BD.     

Disrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia.

BACKGROUND: Converging evidence has demonstrated an association between the Disrupted in Schizophrenia 1 (DISC1) gene and schizophrenia (SZ). Within the DISC1 gene, a single nucleotide polymorphism (SNP), Ser704Cys, has been associated with the structure and function of the hippocampus. Because positive symptoms in SZ have also been associated with hippocampal structure and function, we hypothesized that variation in a DISC1 haplotype containing Ser704Cys would be significantly associated with positive symptomatology in SZ. METHODS: We tested for an association between variation in a haplotype block within the DISC1 gene containing Ser704Cys and lifetime history of positive symptoms in 199 Caucasian patients with SZ. RESULTS: We detected significant associations between a DISC1 haplotype containing Ser704Cys and Ser704Cys genotype and lifetime severity of delusions in SZ. CONCLUSIONS: These data suggest that that the effect of DISC1 genetic variation might be associated with positive symptoms in patients with SZ.     

Association between cerebral dopamine neurotrophic factor (<Emphasis Type="Italic">CDNF</Emphasis>) 2 polymorphisms and schizophrenia susceptibility and symptoms in the Han Chinese population

Background

Schizophrenia (SZ) is a complex polygenic psychiatric disorder caused in part by abnormal dopamine levels. Cerebral dopamine neurotrophic factor (CDNF) 2 is known to protect and repair the dopaminergic system. Dopamine dysfunction is one of the pathogenesis of SZ. However, the relationship between CDNF2 and SZ has not been previously investigated. We speculated that CDNF2 may be a susceptibility factor for SZ.

Methods

To address this issue, we carried out a study to investigate the association between CDNF2 and SZ in the total sample 1371 (670 SZ patients and 701 healthy controls) Han Chinese population. Stage 1 included 528 SZ patients and 528 healthy controls; and stage 2 included 142 SZ patients and 173 healthy controls. The allele and genotype frequencies of five single nucleotide polymorphisms (rs2577074, rs2577075, rs2249810, rs6506891, and rs2118343) of CDNF2 were compared between patients and controls.

Results

We found a significant association in allele and genotype frequencies between the two groups at rs2249810 (χ² = 4.38 and 6.45, respectively; P = 0.03 and 0.04, respectively). An association was also observed in males at rs2249810 (χ² = 8.76; P = 0.03). Haplotype TGATC differed between SZ and controls in stage 2 samples (χ² = 6.38; P = 0.01), and rs2118343 genotypes were associated with negative factor scores (F = 4.396; P = 0.01).

Conclusions

These results suggest that rs2249810 and haplotype TGATC of CDNF2 are an SZ susceptibility locus and factor, respectively, and that rs2118343 genotypes are associated with negative symptoms of SZ in the Han Chinese population.

     

Disrupted action monitoring in recent-onset psychosis patients with schizophrenia and bipolar disorder

Schizophrenia patients experience cognitive control disturbances, manifest in altered neural signatures during action monitoring. It remains unclear whether error- and conflict-monitoring disturbances co-occur, and whether they are observed in recent-onset psychosis patients with schizophrenia or bipolar disorder. We tested electrophysiological measures of action monitoring in these patients. Seventy-three schizophrenia patients (SZ), 26 bipolar disorder type I patients (BP), each within one year of psychosis onset, and 54 healthy control subjects (HC) underwent EEG during Stroop task performance. In the trial-averaged EEG at three midline scalp electrodes, the error-related negativity (ERN), error positivity (Pe) and conflict-related N450 were measured. Compared to HC (1) SZ exhibited an attenuated ERN and N450, and Pe unchanged and (2) BP exhibited an attenuated ERN but normal Pe and N450. Between patient groups, SZ showed an attenuated N450; ERN and Pe were not significantly different. A small (n=10) SZ subgroup that was not receiving antipsychotic medication showed normal ERPs. Altered error- and conflict-monitoring occur together in the first-episode schizophrenia patients, and these measures are comparable in patients with the first-episode bipolar disorder. Antipsychotic medication may be associated with altered measures of error-monitoring in schizophrenia.     

急性脑梗死与炎症的关系探讨

目的通过测定急性脑梗死患者血清中炎症标记物白细胞介素-6(interleukin-6,IL-6)、C反应蛋白(C-reactive protein,CRP)含量,探讨其生化指标在急性脑梗死临床诊治中的应用前景及炎症与脑梗死的关系。方法测定60例急性脑梗死患者不同时期及60例健康对照者血清IL-6、CRP含量及NIHSS评分分析炎症与脑梗死的关系。结果血清IL-6、CRP含量在急性脑梗死后逐渐增加,72h达高峰,急性脑梗死患者血清IL-6、CRP含量明显高于对照组(P均0.01)。结论炎症反应可能参与了急性脑梗死的发生,血清高水平IL-6、CRP有望用于预测脑梗死的预后。