Association study and mutational screening of SYNGR1 as a candidate susceptibility gene for schizophrenia.

OBJECTIVE: Synaptogyrin 1 (SYNGR1) is a transmembrane protein of neurotransmitter-containing vesicle. Recently, suggestive association between SYNGR1 intragenic polymorphisms and schizophrenia has been reported in the Indian population. Furthermore, some rare nucleotide changes with a potential pathogenic effect have been found in Indian and Chinese schizophrenia patients. In this study, we have performed an association study and a resequencing analysis in an Italian sample. METHODS: Eight polymorphisms of the SYNGR1 gene were typed in a case-control sample consisting of 274 patients and 335 controls. In parallel, a mutational screening covering all SYNGR1 exons was conducted. RESULTS: Evidence of association has been found for rs715505 (P = 0.028), a marker already reported to be associated with the disease. Resequencing analysis revealed two novel polymorphisms and several rare variants (13 of 16 as new variants), some of which might have relevance for gene expression and function. CONCLUSION: The results of our association study support a contribution of SYNGR1 to schizophrenia susceptibility. In addition, the resequencing analysis evidenced mutations with a potential functional role at the mRNA and/or protein level. Of particular interest is the p.isoc:S26G missense mutation identified in six patients (0.011) and three controls (0.004) which might be involved in the elimination of a potential protein kinase C phosphorylation site.

Effects of interferon-α on the inflammatory response of swine peripheral blood mononuclear cells.

Interferon-α (IFN-α) at low concentrations had been previously shown to control the expression of inflammatory cytokine genes in swine pulmonary alveolar macrophages. In the first part of this study, cultured swine peripheral blood mononuclear cells (PBMCs) were supplemented with IFN-α at low/moderate concentrations, and then stimulated with lipopolysaccharide (LPS). The expression of IFN-α, IFN-γ, IL-1ß, TNF-α, and IL-6 genes was determined by real-time PCR. IFN-α at low/moderate concentrations did not significantly reduce the expression of any cytokine gene under study, with clear trends though to a concentration-dependent reduction of IL-1ß gene expression and to a concentration-dependent increase of IFN-γ gene expression. In vivo, orally administered IFN-α was shown instead to modulate the inflammatory response to early weaning in uncultured PBMCs of specific pathogen-free piglets. As opposed to the in vitro model, the oral IFN-α treatment reduced after weaning the expression of the IFN-γ gene (P < 0.08) and increased that of the IL-1ß gene (P < 0.05). There was also a trend to a reduced expression of both IL-6 and TNF-α. The above modulation of cytokine genes expression and the greater daily mean weight gain of treated piglets highlight important regulatory properties of oral IFN-α in the response to the weaning stress.

Glutamate AMPA receptor subunit 1 gene (GRIA1) and DSM-IV-TR schizophrenia: a pilot case-control association study in an Italian sample.

Glutamatergic dysfunction is one of the major hypotheses for the pathogenesis of schizophrenia. The GRIA1 gene encodes for one (GluR1) of the four (GluR1-4) ionotropic AMPA receptor subunits. GRIA1 is a good candidate gene for susceptibility to schizophrenia since it maps in 5q33, a region where the presence of susceptibility loci has been suggested by independent genome-wide scans and because its expression has been found to be decreased in the brain of some schizophrenia patients. We present data from a case-control association study on the Italian population with eight polymorphisms spanning the whole GRIA1 gene. Single-locus analysis revealed a significantly different allele distribution in cases and in controls of two SNPs (rs707176, 0.41 vs. 0.31, P = 0.009; rs2963944, 0.41 vs. 0.30, P = 0.007), and one microsatellite (rs10631988, allele 9: 0.40 vs. 0.29, P = 0.004). Haplotype analysis showed an increased frequency of a specific haplotype for these markers (C09CC, 0.39 vs. 0.28, P = 0.009). Therefore our data indicate that GRIA1 may be involved in susceptibility to DSM-IV-TR schizophrenia.

Effects of IFN-alpha on the inflammatory response of swine leukocytes to bacterial endotoxin.

Because low-dose interferon-alpha (IFN-alpha) treatment had proved effective in several models of chronic inflammation and autoimmune disease, a possible role of IFN-alpha in modulating the response of swine leukocytes to bacterial endotoxin was investigated in this study. Exposure of swine peripheral blood mononuclear cells (PBMC) to low concentrations of human IFN-alpha caused a strong, dose-dependent decrease in CD14 expression, the lowest level being observed at 5 U/ml IFN-alpha. This result was confirmed if PBMC were later exposed to purified lipopolysaccharide (LPS). A 10-fold lower IFN-alpha concentration (0.5 U/ml) caused the largest reduction of tumor necrosis factor-alpha (TNF-alpha) accumulation in the medium of pulmonary alveolar macrophages (PAM), stimulated with bacterial LPS. At 0.5 U/ml, the expression of the TNF-alpha gene in PAM was also strongly reduced, as opposed to cells pretreated with 50 U/ml IFN-alpha. In contrast, expression of the interleukin-1beta (IL- 1beta) gene was stimulated and that of the IL-6 gene was not significantly affected at both IFN-alpha concentrations. Results point to an important role of IFN-alpha in control of the inflammatory response to bacterial endotoxin in pigs.