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      Novel association between TGFA, TGFB1, IRF1, PTGS2 and IKBKB single-nucleotide polymorphisms and occurrence, severity and treatment response of major depressive disorder

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          Abstract

          Background Activation of the immune system might affect the severity of depressive episodes as well as response to the antidepressant treatment. The purpose of this study was to investigate whether the occurrence of variant alleles of analyzed SNPs are involved in prevalence and progression of depression. Moreover, selected genes and SNPs have not been investigated in context of the disease severity and treatment. Therefore, six polymorphisms were selected: g.41354391A>G-TGFB1 (rs1800469), g.132484229C>A-IRF (rs2070729), g.186643058A>G-PTGS2 (rs5275), g.186640617C>T-PTGS2 (rs4648308), g.70677994G>A-TGFA (rs2166975) and g.42140549G>T–IKBKB (rs5029748). Methods A total of 360 (180 patients and 180 controls) DNA samples were genotyped using TaqMan probes. Results We observed that A/G of the rs2166975 TGFA, A/C of rs2070729 IRF1 and G/T of rs5029748 IKBKB were associated with an increased risk of depression development while the T/T of rs5029748 IKBKB, T/T of rs4648308 PTGS2 and G/G of rs2166975 TGFA reduced this risk. We also stratified the study group according to gender and found that genotype A/G and allele G of the rs2166975 TGFA, G/T of rs5029748 IKBKB as well as C allele of rs4648308 PTGS2, homozygote A/A and allele A of rs5275 PTGS2 were associated with increased risk of depression development in men while homozygote G/G of rs5275 PTGS2 decreased this risk. Moreover, C/T of rs4648308 PTGS2 and A/G of rs5275 PTGS2 was positively correlated with the risk of the disease occurrence in women. Furthermore, a gene–gene analysis revealed a link between studied polymorphisms and depression. In addition, A/A of rs1800469 TGFB1 was associated with earlier age of onset of the disease while G/G of this SNP increased severity of the depressive episode. Interestingly, A/C of rs2070729 IRF1 and T/T of rs5029748 IKBKB may modulate the effectiveness of selective serotonin reuptake inhibitors therapy. In conclusion, studied SNPs may modulate the risk of occurrence, age of onset, severity of the disease and response to the antidepressant treatment.

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          The IRF family transcription factors in immunity and oncogenesis.

          Tomohiko Tamura, Hideyuki Yanai, David Savitsky … (2008)
          The interferon regulatory factor (IRF) family, consisting of nine members in mammals, was identified in the late 1980s in the context of research into the type I interferon system. Subsequent studies over the past two decades have revealed the versatile and critical functions performed by this transcription factor family. Indeed, many IRF members play central roles in the cellular differentiation of hematopoietic cells and in the regulation of gene expression in response to pathogen-derived danger signals. In particular, the advances made in understanding the immunobiology of Toll-like and other pattern-recognition receptors have recently generated new momentum for the study of IRFs. Moreover, the role of several IRF family members in the regulation of the cell cycle and apoptosis has important implications for understanding susceptibility to and progression of several cancers.
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            iNOS-mediated nitric oxide production and its regulation.

            Fugen Aktan (2004)
            This review focuses on the production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) and its regulation under physiological and pathophysiological conditions. NO is an important biological mediator in the living organism that is synthesized from L-arginine using NADPH and molecular oxygen. However, the overproduction of NO which is catalyzed by iNOS, a soluble enzyme and active in its dimeric form, is cytotoxic. Immunostimulating cytokines or bacterial pathogens activate iNOS and generate high concentrations of NO through the activation of inducible nuclear factors, including NFkB. iNOS activation is regulated mainly at the transcriptional level, but also at posttranscriptional, translational and postranslational levels through effects on protein stability, dimerization, phosphorylation, cofactor binding and availability of oxygen and L-arginine as substrates. The prevention of the overproduction of NO in the living organism through control of regulatory pathways may assist in the treatment of high NO-mediated disorders without changing physiological levels of NO. Copyright 2004 Elsevier Inc.
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              Cytokines and major depression.

              Olga Schiepers, Marieke Wichers, Michael Maes (2005)
              In the research field of psychoneuroimmunology, accumulating evidence has indicated the existence of reciprocal communication pathways between nervous, endocrine and immune systems. In this respect, there has been increasing interest in the putative involvement of the immune system in psychiatric disorders. In the present review, the role of proinflammatory cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the aetiology and pathophysiology of major depression, is discussed. The 'cytokine hypothesis of depression' implies that proinflammatory cytokines, acting as neuromodulators, represent the key factor in the (central) mediation of the behavioural, neuroendocrine and neurochemical features of depressive disorders. This view is supported by various findings. Several medical illnesses, which are characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have been reported to be accompanied by depression. In addition, administration of proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been found to induce depressive symptomatology. Administration of proinflammatory cytokines in animals induces 'sickness behaviour', which is a pattern of behavioural alterations that is very similar to the behavioural symptoms of depression in humans. The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently observed in depressive disorders, as proinflammatory cytokines may cause HPA axis hyperactivity by disturbing the negative feedback inhibition of circulating corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic (5-HT) neurotransmission that is concomitant with major depression, cytokines may reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP) through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase (IDO). Although the central effects of proinflammatory cytokines appear to be able to account for most of the symptoms occurring in depression, it remains to be established whether cytokines play a causal role in depressive illness or represent epiphenomena without major significance.
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                Author and article information

                Contributors
                Tomasz Sliwinski
                Journal
                Journal ID (nlm-ta): PeerJ
                Journal ID (iso-abbrev): PeerJ
                Journal ID (pmc): PeerJ
                Journal ID (publisher-id): PeerJ
                Title: PeerJ
                Publisher: PeerJ Inc. (San Diego, USA )
                ISSN (Electronic): 2167-8359
                Publication date (Electronic): 25 February 2020
                Publication date Collection: 2020
                Volume: 8
                Electronic Location Identifier: e8676
                Affiliations
                [1 ]Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz , Lodz, Poland
                [2 ]Department of Medical Biochemistry, Medical University of Lodz , Lodz, Poland
                [3 ]Department of Haemostatic Disorders, Medical University of Lodz , Lodz, Poland
                [4 ]Institute of Psychology, Department of Personality and Individual Differences, University of Lodz , Lodz, Poland
                [5 ]Department of Adult Psychiatry, Medical University of Lodz , Lodz, Poland
                Article
                Publisher ID: 8676
                DOI: 10.7717/peerj.8676
                PMC ID: 7047865
                SO-VID: 24f19b64-1ff0-4f68-ad47-30bdbafaa689
                Copyright © © 2020 Bialek et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                Date received : 17 October 2019
                Date accepted : 3 February 2020
                Funding
                Funded by: Polish National Science Centre
                Award ID: UMO-2015/19/BNZ7/00410
                This study was supported by funding from a scientific research grant from the Polish National Science Centre (No. UMO-2015/19/BNZ7/00410). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Genetics
                Subject: Pharmacology
                Subject: Psychiatry and Psychology
                Subject: Medical Genetics

                Keywords: major depressive disorder,depression,inflammation,cytokines,single nucleotide polymorphism
                Data availability:
                Keywords: major depressive disorder, depression, inflammation, cytokines, single nucleotide polymorphism

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