Role of TNF-α -308G/A Polymorphism in Bipolar Disorder and its Relationship with Clinical and Demographic Variables.

Objective: Gene-environment interactions might play a significant role in the development of bipolar disorder (BD). The objective of the current study was to investigate the association between tumor necrosis factor (TNF)-α -308 G/A polymorphism and BD and conduct a bioinformatics analysis of the protein-protein network of TNF-α. Gene-environment interactions and the relationship between stressful life events (SLEs) and substance abuse with TNF genotypes and other characteristics were analyzed.

Methods: The genomic deoxyribonucleic acid (DNA) of 400 patients with BD and 200 control subjects were extracted and genotyped for TNF-α -308 G/A polymorphism. SLEs and substance abuse were evaluated using the Life Event and Difficulty Schedule (LEDS) and a self-designed substance abuse questionnaire for the events six months prior to the onset of the disease, respectively. Gene-environment interactions were assessed by multiple statistical tools. Bioinformatics analysis of the TNF-α network and its interacting proteins was carried out using STRING and Cytoscape softwares.

Results: Genotyping analysis revealed a significant association between TNF-α -308 G/A polymorphism and BD (p<0.009). Furthermore, analysis of gene-environment interaction revealed a significant association between TNF-α -308 G/A and SLEs (p=0.001) and TNF-α -308 G/A and substance abuse (p=0.001). Three distinct proteins, RELA, RIPK1, and BIRC3, were identified through hub analysis of the protein network.

Conclusion: TNF-α -308 G/A polymorphism is positively associated with BD. SLEs and substance abuse might trigger the early onset of BD. Proteins identified through bioinformatics analysis might contribute to the TNF-α mediated pathophysiology of BD and can be the potential therapeutic targets.