Pro-inflammatory cytokines and their epistatic interactions in genetic susceptibility to schizophrenia

Abstract

BackgroundIn schizophrenia, genetic background may provide a substrate for intrinsic maldevelopment of the brain through environmental influences, by recruiting neurotrophic factors and cytokines, to trigger the changes that lead to impaired neuronal functions. Cytokines being the key regulators of immune/inflammatory reactions are also known to influence the dopaminergic, noradrenergic, and serotonergic neurotransmission. Therefore, functional polymorphisms in cytokine genes may result in imbalances in the pro- and anti-inflammatory cytokine production.MethodsWe screened polymorphisms in pro- and anti-inflammatory cytokine genes using a case-control association study in a South Indian population. The role of allele, genotype, haplotype, and diplotypes of these cytokine genes and their epistatic interactions were assessed in contributing to the risk of developing schizophrenia. Meta-analysis for the reported associations was also monitored for global significance.ResultsThe pro-inflammatory cytokine gene polymorphisms in IL1Ars1800587, IL6rs1800796, TNFArs361525, and IFNGrs2069718 were associated with schizophrenia. The study also provides significant evidence for strong epistatic interactions among pro-inflammatory cytokine genes IL6 and IFNG in the development of schizophrenia. In silico analysis suggested that associated risk variants were indicative of altered transcriptional activity with higher production of IL1α, IL-6, TNF-α, and IFN-ɤ cytokines. Meta-analysis indicated heterogeneity among study population while IL1Ars1800587 was found to be globally significant.ConclusionsIt is important to identify the nature of inflammatory response that can be amplified by the environment, to influence either Th1 response or Th2 response. The associated functional variants in the study are involved with increased expression resulting in higher production of the pro-inflammatory cytokines IL-1α, IL-6, TNF-α, and IFN-γ. The interaction of immunological stressors with these high producer alleles of pro-inflammatory cytokines may suggest that even a lower threshold may be sufficient to induce a resultant chronic effect on the psycho-social and environmental stressors that may result in the development and pathogenesis of schizophrenia. Understanding environmental factors that influence the expression of these pro-inflammatory cytokine genes or their interaction can possibly help in dissecting the phenotypic variation and therapeutic response to antipsychotics in schizophrenia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0569-8) contains supplementary material, which is available to authorized users.

Tumor necrosis factor‐alpha −1031T/C polymorphism is associated with cognitive deficits in chronic schizophrenia patients versus healthy controls

“…The first finding—that TNF‐ α −1031T/C is not significantly associated with the development of schizophrenia—is consistent with two prior studies conducted on a similar Han Chinese population demonstrating that a number of TNF‐ α single nucleotide polymorphisms, such as −238G/A, −308G/A, −857C/T, and −863C/A are not more or less prevalent in schizophrenia as compared to controls (Duan et al, ; Srinivas et al, ). However, some other studies reported that TNF‐ α −308G/A allele is a risk factor for schizophrenia when examined in North Indian, Saudi, Turkish, Pakistani, and Korean populations, indicating a possible interaction between genetic background and environment (Handoko et al, ; Kadasah, Arfin, Rizvi, Al‐Asmari, & Al‐Asmari, ; Luleyap et al, ; Pae et al, ).…”

“…However, some other studies reported that TNF‐ α −308G/A allele is a risk factor for schizophrenia when examined in North Indian, Saudi, Turkish, Pakistani, and Korean populations, indicating a possible interaction between genetic background and environment (Handoko et al, ; Kadasah, Arfin, Rizvi, Al‐Asmari, & Al‐Asmari, ; Luleyap et al, ; Pae et al, ). One main explanation for this discrepancy on the association between TNF‐ α −1031T/C polymorphism and the susceptibility to schizophrenia may be due to ethnic difference, since it appears that the allele frequency of the variant allele C varied markedly from different ethnicities (Duan et al, ; Handoko et al, ; Kadasah et al, ; Luleyap et al, ; Pae et al, ; Srinivas et al, ). The additional factors such as heterogeneity of the schizophrenia diagnosis, small gene effects, and population stratification may be also involved.…”

Tumor necrosis factor-α and -β genetic polymorphisms as a risk factor in Saudi patients with schizophrenia

“…Recent studies have confirmed the association of a large number of single-nucleotide polymorphisms in a variety of genes with schizophrenia susceptibility 6–11. Genes encoding cytokines seem to be good candidate genes for schizophrenia.…”

“…The presence of G at this position defines the mutant allele known as TNF-β * 1 (1-allele), which is associated with higher TNF-α and -β production 28,29. The functional polymorphisms in cytokine genes may result in imbalances in the pro- and anti-inflammatory cytokine production 11. Keeping in view the potential role of these cytokines as the principal mediators of the immune response and the importance of the chromosomal region containing TNF-α and TNF-β genes, the present study was undertaken to examine the association of TNF-α (−308G/A) and TNF-β (+252G/A) polymorphisms with schizophrenia susceptibility in Saudi population.…”

The Clinical Challenge of Autoimmune Psychosis: Learning from Anti-NMDA Receptor Autoantibodies

“…For example, polymorphisms of the innate system genes, like IL1B, IL6, TNF alpha, or interferon, will lead to a bigger release of pro-inflammatory cytokines in response to environmental stressors (47). …”