The role of pro-inflammatory cytokine gene polymorphisms in major depressive disorder: a systematic review

Major depressive disorder (MDD) is a multifactorial psychiatric disorder increasingly associated with immune-inflammatory mechanisms. Pro-inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), 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 TNF-α and IL-1β 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 TNF-α and IL-1β 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 TNF-α rs1800629 and IL-1β 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 TNF-α and IL-1β 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.