Tumor necrosis factor-α (TNF-α) -308G >a promoter polymorphism (rs1800629) promotes Asians in susceptibility to Plasmodium falciparum severe malaria: A meta-analysis

The multifactorial pathogenesis of severe malaria is partly attributed to host genes, such as those encoding cytokines involved in complex inflammatory reactions, namely tumor necrosis factor-alpha (TNF-α). However, the relationship between TNF-α -308G >A gene polymorphism (rs1800629) and the severity of Plasmodium falciparum (P. falciparum) malaria remains unclear, which prompts a meta-analysis to obtain more precise estimates. The present meta-analysis aimed to better understand this correlation and provide insight into its association in populations with different ethnicities. Literature search outcomes included eight eligible articles in which TNF-α -308G >A polymorphism was determined in uncomplicated malaria (UM) and severe malaria (SM) of P. falciparum as represented in the case and control groups. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated in standard homozygous, recessive, dominant, and codominant genetic models. Subgroup analysis was based on ethnicity, i.e., Africans and Asians. The analyses included overall and the modified outcomes; the latter was obtained without the studies that deviated from the Hardy-Weinberg Equilibrium. The significant data also underwent sensitivity treatment but not publication bias tests because the number of studies was less than ten. Interaction tests were applied to differential outcomes between the subgroups. Overall and HWE-compliant analyses showed no significant association between the TNF-α -308G >A polymorphism and susceptibility to P. falciparum SM (ORs = 1.10–1.52, 95%CIs = 0.68–2.79; Pa = 0.24–0.68). Stratification by ethnicity revealed that two significant associations were found only in the Asians favoring SM for dominant (OR = 1.95, 95% CI = 1.06–3.61, Pa = 0.03) and codominant (OR = 1.83, 95% CI = 1.15–2.92, Pa = 0.01) under the random-effects model, but not among the African populations. The two significant Asian associations were improved with a test of interaction with P-value of0.02–0.03. The significant core outcomes were robust. Results of the meta-analysis suggest that TNF-α -308G >A polymorphism might affect the risk of P. falciparum SM, particularly in individuals of Asian descent. This supports ethnicity as one of the dependent factors of the TNF-α -308G >A association with the clinical severity of malaria. Further large and well-designed genetic studies are needed to confirm this conclusion.Author summary: Host genetic factors play important role in the development and progress of severe malaria due to Plasmodium falciparum infection. One of the key factors is the abnormality in the gene that encodes cytokines, particularly tumor necrosis factor-alpha (TNF-α), which are involved in complex inflammatory reactions. However, the relationship between the abnormality of this gene and malaria severity remains unclear. The present meta-analysis aimed to better understand this correlation and provide insight into its association in populations with different ethnicities. The analyses showed no significant association. Stratification by ethnicity revealed that two significant associations were found only in the Asians favoring SM for dominant and codominant, but not among the African populations. Results of the meta-analysis suggest that TNF-α -308G >A might affect the risk of P. falciparum SM, particularly in individuals of Asian descent. This supports ethnicity as one of the dependent factors of the association between the abnormality of this gene and clinical severity of malaria. Further large and well-designed genetic studies are needed to confirm this conclusion.