Relationship between Interleukin-6 Gene Polymorphism and Hippocampal Volume in Antipsychotic-Naïve Schizophrenia: Evidence for Differential Susceptibility?

Abstract

BackgroundVarious lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls.MethodologyWe examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla – MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms.ResultsSchizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women.ConclusionOur first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic-naïve schizophrenia. Moreover, this relationship was antithetical in healthy controls and this effect was observed in men but not in women. Together, these observations support a “differential susceptibility” effect of rs1800795 in schizophrenia pathogenesis mediated through hippocampal volume deficit that is of possible neurodevelopmental origin.

Altered IL-2, IL-6 and IL-8 serum levels in schizophrenia patients with tardive dyskinesia

“…It is also produced by both neurons and microglias, and acts as a neurotrophic factor in the central nervous system (Ringheim et al, 1995). Decreased serum IL-6 level in schizophrenia patients in this study was accordant with Singh et al's (2009) finding , although most groups have reported that plasma levels of IL-6 were elevated in schizophrenia patients than normal control (Miller et al, 2011;Chen et al, 2012;Dunjic-Kostic et al, 2013;Sasayama et al, 2013;Al-Asmari and Khan, 2014;Kalmady et al, 2014;Song et al, 2014) and some other groups have reported no significant differences (Baker et al, 1996). Several factors such as the effect of antipsychotic drugs and the state of patients might be responsible for the discrepancy.…”

Serum vitamin D and hippocampal gray matter volume in schizophrenia

“…Vitamin D is known to modulate inflammation by decreasing the production of pro-inflammatory cytokines and increasing the production of anti-inflammatory cytokines (McCann and Ames, 2008). In particular, interleukin-6 (IL-6), which is high in schizophrenia patients (Miller et al, 2011), also has a negative association with hippocampal volume (Kalmady et al, 2014). Hypovitaminosis D might enhance the IL-6 mediated damage to the hippocampus (Samuelsson et al, 2006), thereby resulting in volume loss.…”

Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia

“…[60][61][62] Moreover, IL6 rs1800795, located in the promoter region, has been associated with increased IL-6 blood levels 61 and with reduced hippocampal volume in antipsychotic-naive patients with schizophrenia. 63 We also propose a predictive genetic model for schizophrenia risk that includes the MyD88, IL6 and IL1B genes, as well as another 2 key genes in the intracellular signalling of the TLR4 pathway: NFKB1 and IRAK. The model identifies different genotype combinations of these 5 genes that allow the classification of patients with schizophrenia and healthy controls with high sensitivity and specificity.…”