Molecular Detection of the -308 G/A Polymorphism in the Tumor Necrosis Factor Alpha (TNFα) Gene Promoter and Its Relationship with the Development of Severe Dengue in Patients from Urabá Subregion, Antioquia-Colombia

Background: dengue fever is a viral infection caused by the Dengue Virus (DENV), a positive-sense RNA virus belonging to Flaviviridae family. The virus is transmitted to humans through the bite of the Aedes aegypti mosquito. Worldwide, between 100 and 400 million cases are reported annually. The infection in humans can cause three clinical forms which are related to severity: dengue without warnings signs, dengue with warnings signs, and severe dengue. Mutations in some genes that code for immune system proteins have been linked to the appearance of severe clinical forms of the disease, including TNF-α. The TNF-α plays a key role in the immunopathogenesis of the disease: mutations in this gene can increase the production of TNF-α, favoring cytokine storms and vascular damage, which is associated with severe clinical forms of the disease. Therefore, it is important to study the immunopathogenesis of the disease in the human to try to predict and control the onset of severe clinical forms and fatal cases. Methods: This study explores the link between TNF-α promoter gene polymorphism and dengue severity. We re-cruited 92 laboratory-confirmed dengue cases, including 30 dengue without warnings signs, 43 dengue with warnings signs, and 19 severe dengue. Genotyping was done using amplification by PCR (polymerase chain reaction), Sanger sequencing, and bio-informatics analysis of the TNF-α gene promoter mutations. A logistic regression assessed the association between -308 G/A TNF-α mutation and dengue severity. Results: the mutated genotype -308 G/A TNF-α was detected in 10.5% of severe cases. Interestingly, Severe cases showed higher odds of carrying the mutation than those without warnings signs. Severe cases were twice as likely to possess this mutation compared to those with warnings signs, however, no statistically significant differences were found. Genotype frequencies were consistent with Hardy-Weinberg equilibrium (p = 0.112). The estimated post hoc statistical power was 11.3%. Conclusions: Although no statistically significant association was detected, the TNF-α -308G/A polymorphism showed a trend toward increased susceptibility to severe dengue, with a higher frequency among severe cases than among patients with or without warnings signs.