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.
Highlights
In 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
It is important to identify the nature of inflammatory response that is amplified by the environment, and may indicate whether the shift will be towards Th1 response or Th2 response
One would presume that the therapeutic response in schizophrenia in South Indian patients may be contributed through immune regulatory pathway
Summary
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. Schizophrenia is a severe and debilitating mental illness, affecting about seven to eight individuals per 1000 of the general population [1] It is characterized by three broad spectrum behavioral domains such as positive symptoms noted as delusions and hallucinations and negative symptoms noted as apathy, anhedonia, social withdrawal, and cognitive domain [2]. These behavioral domains tend to vary in their presentation based on ethnicity, culture, or environmental conditions which might impact treatment and its outcome [3]. Schizophrenia patients experience elevated morbidity from infectious and autoimmune diseases [8] These environmental risk factors recruit cytokines to the brain to mediate inflammatory processes [9]. Cytokines being the key regulator of immune/inflammatory reactions and brain development emerge as a common pathway for genetic and environmental components of schizophrenia
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