{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T20:58:03Z","timestamp":1785445083210,"version":"3.56.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Major depressive disorder (MDD) is a multifactorial psychiatric disorder increasingly associated with immune-inflammatory mechanisms. Pro-inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-\u03b1) and interleukin-1 beta (IL-1\u03b2), have been implicated in the pathophysiology of MDD through their influence on neuroinflammation, neurotransmitter regulation, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. This systematic review aimed to evaluate the association between\n                      <jats:italic toggle=\"yes\">TNF-\u03b1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">IL-1\u03b2<\/jats:italic>\n                      gene polymorphisms and susceptibility to MDD, treatment response, and related clinical outcomes. A systematic literature search was conducted in PubMed, Embase, and ScienceDirect databases from inception to March 2026, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies investigating\n                      <jats:italic toggle=\"yes\">TNF-\u03b1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">IL-1\u03b2<\/jats:italic>\n                      gene polymorphisms in clinically diagnosed MDD patients were included. Case-control studies published in English involving adult human participants were considered eligible. Data regarding study design, population, polymorphisms, and clinical outcomes were extracted and qualitatively synthesized. A total of 172 records were identified, of which nine studies met the inclusion criteria. Included studies primarily investigated\n                      <jats:italic toggle=\"yes\">TNF-\u03b1<\/jats:italic>\n                      rs1800629 and\n                      <jats:italic toggle=\"yes\">IL-1\u03b2<\/jats:italic>\n                      rs16944 polymorphisms across diverse populations. Several studies reported significant associations between these polymorphisms and increased susceptibility to MDD, suicide risk, severity of depressive symptoms, age of onset, and antidepressant treatment response. However, some studies reported no statistically significant associations, indicating heterogeneity across ethnic groups and study populations. Variability in age, medication status, and environmental stressors may have contributed to inconsistent findings. The findings of this systematic review support the involvement of inflammatory cytokine gene polymorphisms in the pathophysiology of MDD, particularly\n                      <jats:italic toggle=\"yes\">TNF-\u03b1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">IL-1\u03b2<\/jats:italic>\n                      variants. These polymorphisms may contribute to depression susceptibility and treatment response through immune-inflammatory mechanisms. Further large-scale, ethnically diverse studies incorporating gene-environment interactions and next-generation sequencing approaches are needed to validate cytokine-related genetic biomarkers in MDD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1097\/fpc.0000000000000609","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T16:01:53Z","timestamp":1781712113000},"page":"177-184","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["The role of pro-inflammatory cytokine gene polymorphisms in major depressive disorder: a systematic review"],"prefix":"10.1097","volume":"36","author":[{"given":"Yuvapriya","family":"Kalidasan","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vettriselvi","family":"Venkatesan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suvarna Jyothi","family":"Kantipudi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Sri Ramachandra Institute of Higher Education and Research"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilangovan","family":"Ramachandran","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Chennai, Tamil Nadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"R1-20260730","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41392-024-01738-y","article-title":"Major depressive disorder: hypothesis, mechanism, prevention and treatment.","volume":"9","author":"Cui","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"R2-20260730","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1002\/hup.2333","article-title":"Plasma levels of interleukin-6 and selective serotonin reuptake inhibitor response in patients with major depressive disorder.","volume":"28","author":"Yoshimura","year":"2013","journal-title":"Hum Psychopharmacol"},{"key":"R3-20260730","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.jad.2011.08.003","article-title":"Interleukin (IL)-6, tumour necrosis factor alpha (TNF-\u03b1) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis and meta-regression.","volume":"139","author":"Liu","year":"2012","journal-title":"J Affect Disord"},{"key":"R4-20260730","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/978-0-585-37970-8_2","article-title":"Major depression and activation of the inflammatory response system.","volume":"461","author":"Maes","year":"1999","journal-title":"Adv Exp Med Biol"},{"key":"R5-20260730","doi-asserted-by":"crossref","first-page":"12050","DOI":"10.1038\/s41598-018-30487-6","article-title":"IL-1\u03b2, IL-6, TNF-\u03b1 and CRP in elderly patients with depression or Alzheimer\u2019s disease: systematic review and meta-analysis.","volume":"8","author":"Ng","year":"2018","journal-title":"Sci Rep"},{"key":"R6-20260730","doi-asserted-by":"crossref","first-page":"2510","DOI":"10.1038\/npp.2010.116","article-title":"Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters.","volume":"35","author":"Zhu","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"R7-20260730","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/j.1749-6632.2012.06633.x","article-title":"Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction.","volume":"1261","author":"Silverman","year":"2012","journal-title":"Ann N Y Acad Sci"},{"key":"R8-20260730","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1017\/S1461145709009924","article-title":"A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder.","volume":"12","author":"Khairova","year":"2009","journal-title":"Int J Neuropsychopharmacol"},{"key":"R10-20260730","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.jad.2013.03.019","article-title":"TNF-alpha-308G>A polymorphism is associated with suicide attempts in major depressive disorder.","volume":"150","author":"Kim","year":"2013","journal-title":"J Affect Disord"},{"key":"R11-20260730","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1097\/YCO.0b013e32834b9db6","article-title":"Inflammatory mechanisms in major depressive disorder.","volume":"24","author":"Raedler","year":"2011","journal-title":"Curr Opin Psychiatry"},{"key":"R12-20260730","doi-asserted-by":"crossref","first-page":"64","DOI":"10.3390\/ph11030064","article-title":"Insights into macrophage heterogeneity and cytokine-induced neuroinflammation in major depressive disorder.","volume":"11","author":"Dey","year":"2018","journal-title":"Pharmaceuticals (Basel)"},{"key":"R13-20260730","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.biopsych.2005.08.001","article-title":"Cortisol, the cortisol-dehydroepiandrosterone ratio, and pro-inflammatory cytokines in patients with current major depressive disorder comorbid with borderline personality disorder.","volume":"59","author":"Kahl","year":"2006","journal-title":"Biol Psychiatry"},{"key":"R14-20260730","doi-asserted-by":"crossref","first-page":"449","DOI":"10.9758\/cpn.2021.19.3.449","article-title":"White matter alterations associated with pro-inflammatory cytokines in patients with major depressive disorder.","volume":"19","author":"Lim","year":"2021","journal-title":"Clin Psychopharmacol Neurosci"},{"key":"R15-20260730","doi-asserted-by":"crossref","first-page":"66","DOI":"10.4103\/jmedsci.jmedsci_124_23","article-title":"Bupropion associated immunomodulatory effects on peripheral cytokines in male with major depressive disorder.","volume":"44","author":"Huang","year":"2024","journal-title":"J. Med. Sci (Taiwan)"},{"key":"R16-20260730","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jad.2018.04.115","article-title":"Different levels of pro- and anti-inflammatory cytokines in patients with unipolar and bipolar depression.","volume":"237","author":"Mao","year":"2018","journal-title":"J Affect Disord"},{"key":"R17-20260730","first-page":"810","article-title":"Interactive effects of the TNF-\u03b1 gene and major depressive disorder on gray matter volume in the visual cortex.","volume":"274","author":"Zhou","year":"2020","journal-title":"J Affect Disord"},{"key":"R18-20260730","first-page":"53","article-title":"Preliminary investigation of two promoter region polymorphisms of the TNFA gene in patients with recurrent depressive disorder.","volume":"14","author":"Jele\u0144","year":"2021","journal-title":"Biomed Rep"},{"key":"R19-20260730","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1007\/s10571-019-00782-5","article-title":"Preliminary study of the impact of single-nucleotide polymorphisms of IL-1\u03b1, IL-1\u03b2 and TNF-\u03b1 genes on the occurrence, severity and treatment effectiveness of the major depressive disorder.","volume":"40","author":"Bialek","year":"2020","journal-title":"Cell Mol Neurobiol"},{"key":"R20-20260730","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1097\/00041444-200309000-00008","article-title":"Possible association between-G308A tumour necrosis factor-alpha gene polymorphism and major depressive disorder in the Korean population.","volume":"13","author":"Jun","year":"2003","journal-title":"Psychiatr Genet"},{"key":"R21-20260730","doi-asserted-by":"crossref","first-page":"133","DOI":"10.14704\/nq.2021.19.7.NQ21095","article-title":"Associations of tumor necrosis factor\u2013\u03b1 G-308A (rs1800629) gene polymorphisms with major depressive disorder.","volume":"19","author":"Kadhum","year":"2021","journal-title":"NeuroQuantology"},{"key":"R22-20260730","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1111\/j.1440-1819.2008.01918.x","article-title":"Increased soluble tumor necrosis factor-\u03b1 receptors in patients with major depressive disorder.","volume":"63","author":"Grassi-Oliveira","year":"2009","journal-title":"Psychiatry Clin Neurosci"},{"key":"R23-20260730","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1046\/j.1365-2249.1996.d01-647.x","article-title":"Tumour necrosis factor-alpha (TNF-\u03b1) gene polymorphism and expression in pre-eclampsia.","volume":"104","author":"Chen","year":"1996","journal-title":"Clin Exp Immunol"},{"key":"R24-20260730","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1038\/sj.npp.1300172","article-title":"Association study of the interleukin-1beta (C-511T) genetic polymorphism with major depressive disorder, associated symptomatology, and antidepressant response.","volume":"28","author":"Yu","year":"2003","journal-title":"Neuropsychopharmacology"},{"key":"R25-20260730","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s12031-011-9507-5","article-title":"Interleukin-1beta promoter (-31T\/C and -511C\/T) polymorphisms in major recurrent depression.","volume":"44","author":"Borkowska","year":"2011","journal-title":"J Mol Neurosci"},{"key":"R26-20260730","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1007\/s12017-009-8078-x","article-title":"Interleukin-1 beta -511C\/T genetic polymorphism is associated with age of onset of geriatric depression.","volume":"11","author":"Hwang","year":"2009","journal-title":"Neuromolecular Med"},{"key":"R27-20260730","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"R28-20260730","doi-asserted-by":"crossref","first-page":"e0319844","DOI":"10.1371\/journal.pone.0317665","article-title":"Association of IL-1\u03b2 gene polymorphisms with major depressive disorder in the Bangladeshi population.","volume":"20","author":"Toma","year":"2025","journal-title":"PLoS One"},{"key":"R29-20260730","doi-asserted-by":"crossref","first-page":"pyv006","DOI":"10.1093\/ijnp\/pyv006","article-title":"NLRP3 inflammasome mediates chronic mild stress-induced depression in mice via neuroinflammation.","volume":"18","author":"Zhang","year":"2015","journal-title":"Int J Neuropsychopharmacol"},{"key":"R30-20260730","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1093\/ijnp\/pyac079","article-title":"Inflammation and blood-brain barrier in depression: interaction of CLDN5 and IL6 Gene variants in stress-induced depression.","volume":"26","author":"Gal","year":"2023","journal-title":"Int J Neuropsychopharmacol"}],"container-title":["Pharmacogenetics and Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.1097\/FPC.0000000000000609","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T20:00:45Z","timestamp":1785441645000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.1097\/FPC.0000000000000609"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":29,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.1097\/fpc.0000000000000609","relation":{},"ISSN":["1744-6872","1744-6880"],"issn-type":[{"value":"1744-6872","type":"print"},{"value":"1744-6880","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]},"assertion":[{"value":"2025-03-27","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-23","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}