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.

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.

Introduction: Major depressive disorder (MDD) is a common comorbidity of type 2 diabetes (T2D) with low rates of treatment response to antidepressants. The pathophysiology of these conditions overlaps in N-methyl-d-aspartate receptors (NMDARs), which are present in neurons and pancreatic cells. GRIN1 encodes NMDARs and has been associated with depression and T2D; however, its role in the coexistence of MDD and T2D and the treatment response to antidepressants has yet to be explored. Objective: We aimed to evaluate the association between GRIN1 rs28489906 and MDD and treatment response to antidepressants in patients with T2D. Methods: A prospective study was conducted on T2D patients enrolled in a comprehensive care program with follow-up at 3 months. Subjects were assessed for MDD, and genotyping for GRIN1 rs28489906 was performed. Depression scores and glycated hemoglobin (HbA1c) were analyzed using the Wilcoxon paired signed-rank test, and a stratified analysis was conducted to assess treatment response. Logistic regression analyses were performed to predict MDD and treatment response. Results: Our sample included 232 patients; among them, 49 (21%) had MDD. Patients with MDD showed a higher frequency of the AA genotype compared with non-MDD subjects (p = 0.026). A allele carriers reported lower treatment response rates (p = 0.049) and decreased odds of treatment response (OR = 0.03, 95% CI 0.002–0.63, p = 0.023). Patients with AG and AA genotypes with treatment response exhibited lower HbA1c (p = 0.029). Conclusions: The A allele of GRIN1 rs28489906 was associated with MDD and treatment response in patients with T2D. Our findings highlight the role of glutamate in these comorbidities and the need for different therapeutic approaches based on genetics.