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.

中文翻译：

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肿瘤坏死因子-α (TNF-α) -308G >a 启动子多态性 (rs1800629) 促进亚洲人对恶性疟原虫严重疟疾的易感性：一项荟萃分析。

严重疟疾的多因素发病机制部分归因于宿主基因，例如编码参与复杂炎症反应的细胞因子的基因，即肿瘤坏死因子-α（TNF-α）。然而，TNF-α -308G >A 基因多态性 (rs1800629) 与恶性疟原虫 (P. falciparum) 疟疾严重程度之间的关系仍不清楚，这促使进行荟萃分析以获得更精确的估计。本荟萃分析旨在更好地理解这种相关性，并深入了解其在不同种族人群中的关联。文献检索结果包括 8 篇符合条件的文章，其中在病例组和对照组中恶性疟原虫的单纯性疟疾 (UM) 和重症疟疾 (SM) 中确定了 TNF-α -308G >A 多态性。在标准纯合、隐性、显性和共显性遗传模型中估计了合并比值比 (OR) 和 95% 置信区间 (95% CI)。亚组分析基于种族，即非洲人和亚洲人。分析包括总体结果和修改后的结果；后者是在没有偏离哈代-温伯格平衡的情况下获得的。重要数据也经过了敏感性处理，但没有进行发表偏倚测试，因为研究数量少于十个。交互作用测试适用于亚组之间的差异结果。总体分析和符合 HWE 的分析显示 TNF-α -308G >A 多态性与恶性疟原虫 SM 易感性之间没有显着关联（OR = 1.10-1.52，95% CI = 0.68-2.79；Pa = 0.24-0.68）。按种族分层显示，仅在支持 SM 的亚洲人中发现两种显着关联：显性（OR = 1.95，95% CI = 1.06-3.61，Pa = 0.03）和共显性（OR = 1.83，95% CI = 1.15-2.92， Pa = 0.01）在随机效应模型下，但在非洲人群中则不然。通过 P 值为 0.02-0.03 的交互作用测试，两个显着的亚洲关联性得到了改善。重要的核心成果是稳健的。荟萃分析的结果表明，TNF-α -308G >A 多态性可能会影响恶性疟原虫 SM 的风险，特别是在亚洲血统的个体中。这支持种族是 TNF-α -308G >A 与疟疾临床严重程度相关的依赖因素之一。需要进一步大规模且精心设计的遗传学研究来证实这一结论。