Abstract
Individual studies have assessed the association between TNF-α-308G>A and TNF-α-238 G>A polymorphisms and severity of dengue infection. However, the results are inconclusive and most studies had small sample sizes. The objective of this study was to summarize the evidence of association between TNF-α-308 G>A and TNF-α-238 G>A and severity of dengue infection.This study follows the preferred reporting items for systematic reviews and meta- analyses of genetic association studies, recommended by PLOS One. We calculated pooled odds ratio and its 95% confidence interval (CI) to estimate the association between TNF-α-308 G>A or TNF-α-238 G>A and the risk of severe dengue infections. To determine the information size required for this meta-analysis study, a trial sequential analysis (TSA) was done. Eight studies (640 cases and 1275 controls), which assessed the association of TNF-α-308 G>A or TNF-α-238 G>A and the risk of DHF were included. Overall, we found no significant association between TNF-α-308 G>A and the DHF risk in the allelic model (OR, 0.91; 95% CI, 0.51–1.63), the recessive model (OR,1.32;95%CI,0.73–2.37), the dominant model (OR,0.93;95%CI:0.59–1.47) or the additive model (OR,1.43,95;95%CI:0.79–2.59). There was also no significant association between TNF-α-238 G>A and DHF risk under the allele contrast model (OR:1.51;95%CI:0.88–2.58), the recessive model (OR,1.48,95% CI:0.33–6.58), the dominant model (OR,1.48;95%CI:0.56–3.92), or the additive model (OR:1.5;95%CI:0.34–6.69). On subgroup analysis, neither the Asian population nor the non-Asian population showed significant association between TNF-α-308 G>A/TNF-α-238 G>A and the DHF risk under any genetic models. Leave-one-out meta-analysis showed stability of the results. TSA plots suggested that the sample size in this meta-analysis study was below the required information size.The findings suggest an inclusive evidence of the association between TNF-α-308/ TNF-α-238 G>A and the risk of developing severe dengue infection. Large studies with evidence of Hardy-Weinberg equilibrium, assessing gene-gene interactions are recommended.
Highlights
Dengue fever is endemic in the tropics and sub-tropics and it is the most common arboviral infection caused by dengue viruses (DENV-1, -2, -3, and -4), which are transmitted primarily by the bite of Aedes aegypti and Ae. albopictus mosquitoesThe clinical manifestations of DENV infection vary from mild to the severe form of dengue haemorrhagic fever (DHF)
The current study conformed to the checklist for meta-analysis of genetic association studies specified for PLOS One approach [13] (S1 Table)
We found no significant association between TNF-α-308 G>A polymorphism and the risk of DHF in allelic genetic models (OR: 1.08, 95%confidence interval (CI): 0.49–2.37, I2: 83%) (S5 Table)
Summary
Dengue fever is endemic in the tropics and sub-tropics and it is the most common arboviral infection caused by dengue viruses (DENV-1, -2, -3, and -4), which are transmitted primarily by the bite of Aedes aegypti and Ae. albopictus mosquitoesThe clinical manifestations of DENV infection vary from mild (asymptomatic, undifferentiated fever, dengue fever) to the severe form of dengue haemorrhagic fever (DHF). It is estimated that 2.5 billion people worldwide are at risk for DENV infection. About 5% of those at risk will have severe forms such as DHF and dengue shock syndrome (DSS), which are potentially fatal [1,2]. The exact pathogenesis of progression from mild to severe forms of dengue infections is not known. A number of studies have suggested that leakage of plasma, which differentiates DHF from DF is attributed to the direct and indirect effects of cytokines or chemical mediators on the vascular endothelial cells [3,4,5]. TNF-α has been implicated in the process of plasma leakage and shock [6]
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