A replication study of sHLA-E influence on schizophrenia and bipolar disorder.

OBJECTIVES: Schizophrenia (SZ) and bipolar disorders (BP) are chronic and severe neuropsychiatric diseases. These disorders are tightly related to immune deregulations. In the current study, we intended to replicate the previously reported involvement of the soluble HLA-E isoforms (sHLA-E) in the risk of developing the two conditions along with disease severity in a Tunisian population group. PATIENTS AND METHODS: One hundred and twenty-four patients with schizophrenia and 121 with bipolar disorder meeting the DSM-IV criteria along 111 healthy controls were included in this present case-control study. The soluble HLA-E isoforms circulating levels were measured using the ELISA method. The statistical analyses were performed using Kruskal-Wallis and Wilcoxon rank sum tests by R software and GraphPad prism 9. RESULTS: We found that the sHLA-E circulating levels were significantly higher in BP patients as compared to healthy controls (P<0.0001) and that such increases were mainly observed in patients during an acute phase of their disease (P<0.0001). In SZ patients, while we failed to observe an association with the levels of sHLA-E in the entire SZ sample, we found that high sHLA-E levels characterized stabilized patients in comparison with those during an acute episode (P=0.022). Finally, we did not observe any association between sHLA-E circulating levels and symptoms assessed by the classical clinical scales either in BP or SZ patients. CONCLUSION: Overall, the present findings replicate in a Tunisian population group the previously demonstrated implication of sHLA-E circulating levels in the risk of developing BP or SZ in a French patient cohort. Such replication allows to consider HLA-E as a potent and true inflammatory marker in the context of the two disorders.

Association between genetic variants of TLR2, TLR4, TLR9 and schizophrenia.

BACKGROUND AND STUDY AIM: Schizophrenia (SZ) is a multifactorial disorder involving complex interactions between genetic and environmental factors, where immune dysfunction plays a key etiopathogenic role. In order to explore the control of innate immune responses in SZ, we aimed to investigate the potential association between twelve TLR2, TLR4 and TLR9 variants (TLR2: rs4696480T>A, rs3804099T>C, rs3804100T>C; TLR4: rs1927914G>A, rs10759932T>C, rs4986790A>G, rs4986791T>C, rs11536889G>C, rs11536891T>C; TLR9: rs187084A>G, rs352139T>C and rs352140C>T) and SZ susceptibility in a Tunisian population. PATIENTS AND METHODS: This study included 150 patients and 201 healthy controls with no history of psychiatric illness. Genotyping was done using a TaqMan SNP genotyping assay. We also assessed a haplotype analysis for TLR2, TLR4 and TLR9 variants with SZ using Haploview 4.2 Software. RESULTS: We found that the AA genotype of the TLR2 rs4696480T>A variant was significantly associated with an increased risk of SZ (46% vs. 31%, P=4.7×10-3, OR=1.87 and 95% CI [1.18-2.97]). The frequency of the TA genotype was significantly higher in the control group than in SZ patients (27% vs. 43%, P=2.1×10-3) and may be associated with protection against SZ (OR=0.49 and 95% CI [0.30-0.80]). Whereas, the TLR9 rs187084-GG genotype was higher in the control group compared to patients (16% vs. 5%, P=1.6×10-3) and would present protection against SZ (OR=0.28, CI=[0.10-0.68]). The ACT haplotype of the TLR2 and the ACC haplotype of the TLR9 gene were identified as a risk haplotypes for SZ (P=0.04, OR=9.30, 95% CI=[1.11-77.71]; P=3×10-4, OR=6.05, 95% CI=[2.29-15.98], respectively). CONCLUSION: The results indicate that TLR2 and TLR9 genetic diversity may play a role in genetic vulnerability to SZ. However, including more patients and evaluation of TLR2 and TLR9 expression are recommended.

CSMD1 rs10503253 increases schizophrenia risk in a Tunisian population-group.

OBJECTIVES: Schizophrenia is a complex and chronic neuropsychiatric disorder. Recent genome-wide association studies have identified several at risk genetic variants, including two single nucleotide polymorphisms, namely the rs10503253 and the rs1270942 respectively located in the CSMD1 and the CFB loci. The present case-control study was designed to assess potential associations between the two variants and the risk of developing schizophrenia and disease severity. Further we demonstrate the relationship between these variants and clinical characteristics in a population-group from Tunisia. PATIENTS AND METHODS: In total, 216 patients diagnosed with schizophrenia along with176 healthy controls were included in this case-control study. The molecular analysis of the two polymorphisms was performed using tetra the Primer Amplification Refractory Mutation System-Polymerase Chain method. The statistical analysis was done using Compare V2.1 software, and correlations between genetic results and clinical characteristics were examined by Kruskal-Wallis testing. RESULTS: The frequency of the rs10503253A allele was found significantly higher among patients with schizophrenia as compared to healthy controls and associated with high negative PANSS scores. While no association was found concerning the implication of the rs1270942 variant in schizophrenia risk, a positive correlation with high positive PANSS scores was further observed. CONCLUSION: The present finding confirms the previously reported association between the Cub and Sushi multiple Domain 1 rs10503253A allele and the risk to develop schizophrenia and identified the rs1270942 variant as a potential disease risk modifier. Such observations may be important for the definition of the susceptible immunogenetic background in North African individuals at risk to develop mental disorders.

Low peripheral mitochondrial DNA copy number during manic episodes of bipolar disorders is associated with disease severity and inflammation.

Mitochondria (Mt) are intra-cellular components essential for cellular energy processes whose dysfunction may induce premature cellular senescence and/or inflammation, both observed in bipolar disorders (BD). We investigated mitochondrial DNA copy number (mtDNAcn) levels in patients with BD being in manic, depressive or euthymic phase and in healthy controls (HC) both characterized for the levels of blood-based inflammatory markers and stigma of pathogens. 312 patients with BD were compared to 180 HC. mtDNAcn were measured using a digital droplet PCR. Serum levels of 14 inflammatory molecules and 3 anti-infectious IgG stigma were respectively evaluated by electro-chemiluminescence, ELISA and dedicated immunoassays. The statistical analyses were performed using Spearman's correlation, Wilcoxon signed-rank and Kruskal-Wallis rank sum tests. P-values were adjusted for multiple testing with Benjamini-Hochberg method. We found low levels of mtDNAcn in BD patients as compared to HC (P = 0.008) especially during manic episodes (P = 0.0002). We also observed that low levels of mtDNAcn are negatively correlated with mood and psychotic scales (PANSS, YMRS and CGI) (adjusted P (Adj P) = 0.02, 0.003 and 0.05 respectively) and positively with the GAF severity scale (Adj P = 0.002). They were also correlated with high levels of both intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 (Adj P = 0.003 and 0.001) along with a trend toward increased IL-2, IL-10 and B2M circulating levels (Adj P = 0.05). Here, we report correlations between marker of mitochondria functioning and both clinical scales and inflammatory markers in BD patients experiencing manic episodes. If replicated, these finding might allow to predict transition between disease phases and to design accurate therapeutic options.

High-Sensitive c-Reactive Protein Levels in Euthymic Bipolar Patients: Case-Control Study.

Bipolar disorder is a chronic, disabling disease that is characterized by the recurrence of thymic episodes. The role of the immune-inflammatory system in the etiopathogenesis of this affection arouses the interest of research. The aim of this work was to determine the plasma levels of the high sensitivity C reactive protein (hs-CRP) in patients with bipolar disorder in remission phase by comparing them to a control group.A case-control cross-sectional study was conducted from 56 subjects with bipolar disorder in clinical remission, and 56 volunteers and healthy control subjects.Mean plasma hs-CRP was significantly higher in patients with bipolar disorder than control subjects. In bipolar patients, a hs-CRP elevation was significantly associated with the disease severity item mean score.Through this study, bipolar disorder appears to be associated with a state of chronic inflammation. This should lead to randomized controlled trials evaluating the value of anti-inflammatory drugs in the management of bipolar disorder.