Tumour necrosis factor allele variants and their association with the occurrence and severity of malaria in African children: a longitudinal study

Background: Tumour necrosis factor (TNF) is central to the immune response to Plasmodium infection. Its plasma concentration is influenced by allele variants in the promoter region of TNF. The study's objectives were to assess TNF allele variants (TNF-1031, TNF-308): (1) modulation of malaria rates in young Tanzanian children; (2) modulation of the severity of malaria as indicated by haemoglobin concentrations at the time of presentation with febrile episodes; and (3) the association between Plasmodium infection and haemoglobin concentration in symptomless parasite carriers. Methods: Data from a placebo-controlled trial in which 612 Tanzanian children aged 6-60 months with height-forage z-score in the range -3 SD to 1.5 SD was utilised. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. An episode of malaria was predefined as current Plasmodium infection with an inflammatory response (axillary temperature >= 37.5 degrees C or whole blood C-reactive protein concentration >= 8 mg/L) in children reported sick. Linkage disequilibrium (LD) pattern assessment as well as haplotype analysis was conducted using HAPLOVIEW. Cox regression models used in the primary analysis accounted for multiple episodes per child. Results: Genotyping of 94.9% (581/612) children for TNF-1031 (TNF-1031T>C); allele frequency was 0.39. Corresponding values for rs1800629 (TNF(-308)G>A) were 95.4% (584/612) and 0.17. Compared to the wild type genotype (TT), malaria rates were increased in the TNF-1031CC genotype (hazard ratio, HR [95% CI]: 1.41 [1.01-1.97] and 1.31 [0.97-1.76] for crude analysis and adjusting for pre-specified baseline factors, respectively) but decreased in those with the TNF(-308)AA genotype (corresponding HR: 0.13 [0.02-0.63] and 0.16 [0.04-0.67]). These associations were weaker when analysing first episodes of malaria (P value-0.59 and 0.38, respectively). No evidence that allele variants of TNF-1031 and TNF-308 affected haemoglobin concentration at first episode of malaria, or that they modified the association between Plasmodium infection and haemoglobin concentrations at baseline was observed. Conclusion: In this cohort of Tanzanian children, the TNF-1031CC genotype was associated with increased rates of malarial episodes, whereas the TNF(-308)AA genotype was associated with decreased rates.