title: Tumour necrosis factor allele variants and their association with the occurrence and severity of malaria in African children: a longitudinal study.
abstract: 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-for-age 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°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(-1031)T>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.
  
  
  CONCLUSIONS
  In this cohort of Tanzanian children, the TNF (-1031)CC genotype was associated with increased rates of malarial episodes, whereas the TNF(-308)AA genotype was associated with decreased rates.
authors.affiliation: Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. wngichohi@gmail.com.
authors.forename: Wanjiku N
authors.initials: WN
authors.lastname: Gichohi-Wainaina
authors.affiliation: Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. Alida.melse@wur.nl.
authors.forename: Alida
authors.initials: A
authors.lastname: Melse-Boonstra
authors.affiliation: Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands. Edith.feskens@wur.nl.
authors.forename: Edith J
authors.initials: EJ
authors.lastname: Feskens
authors.affiliation: Laboratory for Clinical Chemistry, Meander Medical Centre, Amersfoort, The Netherlands. AY.Demir@meandermc.nl.
authors.forename: Ayse Y
authors.initials: AY
authors.lastname: Demir
authors.affiliation: Laboratory for Microbiology and Infection Control, Amphia Hospital, Breda, The Netherlands. Jacobien.Veenemans@gmail.com.
authors.forename: Jacobien
authors.initials: J
authors.lastname: Veenemans
authors.affiliation: Cell Biology and Immunology Group, Wageningen University, Wageningen, The Netherlands. Hans.Verhoef@icloud.com.|Medical Research Council (MRC) International Nutrition Group, London School of Hygiene & Tropical Medicine, London, UK. Hans.Verhoef@icloud.com.|Medical Research Council (MRC), Keneba, The Gambia. Hans.Verhoef@icloud.com.
authors.forename: Hans
authors.initials: H
authors.lastname: Verhoef
mesh_terms: D058345:Asymptomatic Infections / Q000453:epidemiology; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D006454:Hemoglobins / Q000032:analysis*; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D008288:Malaria / Q000453:epidemiology / Q000469:parasitology*; D008297:Male; D010961:Plasmodium / Q000502:physiology*; D013636:Tanzania / Q000453:epidemiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D006454:Hemoglobins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha