Carlo Esteban Sotelo-Ramírez

Clinical and genetic studies have suggested that immune dysregulation and neuroinflammation are involved in the pathogenesis of schizophrenia. Peripheral laboratory markers are accessible indicators linked to systemic inflammation and immune function. Genetic studies have demonstrated that blood parameters are highly heritable. Therefore, the aim of this study was to analyze the association between blood parameters and IL10, TNF, TLR2, and TLR6 gene polymorphisms in Mexican patients with schizophrenia. We included 236 Mexican patients with schizophrenia. Peripheral blood samples were obtained in the early morning, prior the breakfast, from each participant. Complete blood count was analyzed. Genomic DNA was extracted, and genotyping was performed using TaqMan Discrimination assay of IL10 (rs1554286), TNF (rs1800629), TLR2 (rs7656411), and TLR6 (rs5743827). Association analyses between blood parameters and genotypes of the four genetic variants were performed using chi-square tests and ANOVA with Tukey’s post-hoc multiple comparisons. We observed higher monocyte levels (F = 5.57; p = 0.004) and monocyte-lymphocyte ratio (F = 5.49; p = 0.004) in patients carrying the GG genotype of rs7656411/TLR2 compared with TT or TG genotype carriers. Additionally, we observed a high frequency of the G allele of rs1800629/TNF, showing a low platelet count compared with carriers of the A allele (χ2 = 8.6, p = 0.003; OR = 3.82; CI, 1.46–9.96). Furthermore, we were unable to detect any gene-gene interaction in the analysis of MPV and platelet count after 1000-fold permutation testing. Our findings indicate that blood parameter levels may be affected by genetic variants of TNF and TLR2 genes, indicating a potential role for innate immune response activation in schizophrenia in the Mexican population. Further studies with larger cohorts and comprehensive genetic analyses are essential to validate these findings and clarify the role of innate immune genes in schizophrenia.

The pharmacological maintenance treatment for bipolar disorder patients depends on mood stabilizers such as lithium and valproate. An association between GRIN2B and NTRK2 gene polymorphisms and treatment response to lithium and valproate has been reported. Therefore, we examined the relationship between polymorphisms of GRIN2B and NTRK2 and the long-term treatment response to valproate and lithium in bipolar disorder patients. We performed a genetic association study involving bipolar disorder patients treated with valproate and lithium, along with a control group. The long-term treatment response was retrospectively assessed using Alda's scale. Genotyping of GRIN2B (rs1806201, rs890) and NTRK2 (rs2289656) was conducted with allele discrimination TaqMan assays. We analyzed 251 bipolar disorder patients, 130 treated with valproate and 121 with lithium, and 300 controls. The analysis, which controlled for sex and age as covariates, observed an association between rs1806201 and BD (p = 0.003). The analysis of treatment response showed an effect of the NTRK2/rs2289656 and treatment response to valproate, with the number of depressive, hypomanic, psychotic, and mixed episodes as covariates (p = 0.043). No association was found between the two genes analyzed and the response to lithium treatment. Our findings suggest that GRIN2B and NTRK2 may play a crucial role in the cause of bipolar disorder. The analysis of treatment response revealed a link between the NTRK2 gene and valproate response in BD patients. However, our results did not reproduce the association of these two genes with lithium response in Mexican patients.

Schizophrenia (SZ) is a chronic disabling mental disorder with high heritability, and several immune-regulating genes have been implicated in its pathophysiology In this study, we investigated the expression of Toll-like receptors (TLRs) 1, 2, and 6 in peripheral blood monocytes from SZ patients and healthy control subjects (HCSs) in the Mexican population, focusing on specific SZ-associated gene variants. Gene expressions were assessed by qPCR, and protein expression was measured using flow cytometry. The secretory profiles of MALP2-stimulated monocytes were evaluated through immunoproteomic arrays. Our results indicate that patients with SZ carrying the rs4833093/TLR1 GG genotype exhibited significantly lower TLR1 gene expression compared to TT carriers. Notably, HCSs with the TT genotype showed markedly higher TLR1 protein expression, while all patients with SZ exhibited significantly reduced protein levels regardless of genotype. Furthermore, monocytes from patients with SZ displayed altered secretion profiles upon TLR stimulation, with significant elevations in IL-18, uPAR, angiopoietin-2, and serpin E1, alongside reductions in MCP-1, IL-17A, IL-24, MIF, and myeloperoxidase compared to HCSs. These findings suggest a dysfunctional TLR-mediated innate immune response in SZ.

Background: Hypothalamic-pituitary-adrenal axis gene variants and childhood trauma (CT) are considered risk factors for suicide attempt (SA). The aim of the present study was analyzed gene x environment (GxE) interaction of NR3C1, NR3C2, and CT, and NR3C1 and NR3C2 gene expression in the development of SA with CT. Participants and Methods: A total of 516 psychiatric Mexican patients from Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz. Among them, 274 had SA at least once and 242 had not SA. Genetic variants of NR3C1 and NR3C2 were genotyped in all the patients, of which were obtained the CT information from medical records. Additionally, the gene expression of NR3C1 and NR3C2 was also analyzed for a subsample of 96 patients, obtaining the TC information from Childhood Trauma Questionnaire (CTQ). Results: The analysis showed a GxE interaction of NR3C1, NR3C2, and CT (OR=2.8, 95% CI [1.9– 3.9], p< 0.0001). Interactions were also observed with neglect (OR=2.1, 95% CI [1.4– 3.1], p< 0.0001), emotional abuse (OR=2.1, 95% CI [1.5– 3], p< 0.0001), and sexual abuse (OR=2.4, 95% CI [1.4– 2.9], p< 0.0001) in the prediction of SA. The analysis of gene expression identified an overexpression of NR3C1 in SA patients with high scores for physical and sexual abuse (p< 0.0001; p< 0.0006, respectively) and emotional neglect (p=0.014). An underexpression was observed of NR3C2, associated with high scores of trauma subtypes (p< 0.0001) except physical neglect. Additionally, we observed an overexpression of NR3C1 gene in patients with SA carriers of A allele of rs6191 (p=0.0015). Also, overexpression of NR3C1 gene in carriers of G allele of rs6198 and underexpression of NR3C2 gene in carriers of G allele of rs5522 (p< 0.0001). Conclusion: Our findings suggest that genetic variants of NR3C1 and NR3C2 differentially affect expression levels, increasing the susceptibility to SA in psychiatric patients with a history of CT.

Introduction: Schizophrenia is a complex psychiatric disorder with an important genetic contribution. Immunological abnormalities have been reported in schizophrenia. Toll-like receptor (TLR) genes play an important role in the activation of the innate immune response, which may help to explain the presence of inflammation in people with this disorder. The aim of this study was to analyze the association of TLR1, TLR2, and TLR6 gene polymorphisms in the etiology of schizophrenia. Methods: We included 582 patients with schizophrenia and 525 healthy controls. Genetic analysis was performed using allelic discrimination with TaqMan probes. Results: We observed significant differences between patients and controls in the genotype and allele frequencies of TLR1/rs4833093 (χ 2 = 17.3, p = 0.0002; χ 2 = 15.9, p = 0.0001, respectively) and TLR2/rs5743709 (χ 2 = 29.5, p = 0.00001; χ 2 = 7.785, p = 0.0053, respectively), and in the allele frequencies of TLR6/rs3775073 (χ 2 = 31.1, p = 0.00001). Finally, we found an interaction between the TLR1/rs4833093 and TLR2/rs5743709 genes, which increased the risk of developing schizophrenia (OR = 2.29, 95% CI [1.75, 3.01]). Discussion: Our findings add to the evidence suggesting that the activation of innate immune response might play an important role in the development of schizophrenia.

Insights into myelin dysfunction in schizophrenia and bipolar disorder

Family, twin, and adoption studies have suggested that genetic factors might be involved in suicidal behavior. Corticotropin-releasing receptor type 1 (CRHR1) and 2 (CRHR2) genes play a key role in the activation and modulation of the hypothalamic–pituitary–adrenal (HPA) axis, which is considered a major stress regulator. Childhood trauma is an environmental risk factor associated with suicide attempt (SA) and it has been related to HPA axis dysregulation. This study aimed at analyzing the relationship of CRHR1 and CRHR2 genes with childhood trauma concerning the development of SA. In this study, we included 366 affective disorder patients. Among them, 183 patients had SA at least once and 183 had not SA. Information regarding SA and childhood trauma was obtained from medical records. Multifactor Dimensionality Reduction program was used to detect gene–environment interactions between CRHR1 (rs110402, rs242924, and rs16940665) and CRHR2 (rs2190242, rs2284217, and rs2014663) with childhood trauma in SA. The analysis showed an interaction of CRHR1 and CRHR2 with childhood trauma, thus conferring increased risk of having presented at least one SA (OR 7.44; 95% CI 4.58–12.07; p < 0.0001). In addition, we observed the following in the trauma subtypes analysis: physical negligence (OR 4.72; 95% CI 3.01–7.40; p < 0.0001), emotional abuse (OR 5.76; 95% CI 3.67–9.05; p < 0.0001), and sexual abuse (OR 5.70; 95% CI 3.62–8.97; p < 0.0001). Our results suggested that genetic variants of CRHR1 and CRHR2 genes in addition to physical negligence, and emotional and sexual abuse, contribute to increase risk of presented at least one SA.