title: Genetic evidence for the aggravation of Plasmodium falciparum malaria by interleukin 4.
abstract: BACKGROUND
  Severe malaria (SM) due to Plasmodium falciparum causes millions of child deaths in sub-Saharan Africa. It comprises a variety of clinical disorders, including cerebral malaria (CM) and severe anemia (SA). In previous work, we have shown that interferon gamma and interleukin 12 protect against CM. Here, we investigated whether interleukin 4 (IL-4) aggravates the risk of severe disease.
  
  
  METHODS
  We prospectively recruited children with CM (n = 240), SA (n = 101), and uncomplicated malaria (UM) (n = 42) in Bamako, Mali, and measured IL-4 production in plasma by enzyme-linked immunosorbent assay. We then assessed the influence of 11 polymorphisms on predisposition to SM by the family-based association test (FBAT).
  
  
  RESULTS
  IL-4 concentrations were higher in children with CM than in children with UM during malaria (P = .003). FBAT analyses showed that the most significant association was between the IL4 variable-number tandem repeat (VNTR) 1/2 genotype and SM (P < .001); an association was also observed for IL4 -33 C/T, rs2243267 G/C, rs2243268 C/A, and rs2243282 C/A (P < .05). Interestingly, we found that the plasma concentration of IL-4 was higher in subjects with the IL4 VNTR 1/2 or 1/1 genotype than with the IL4 VNTR 2/2 genotype (P = .003).
  
  
  CONCLUSIONS
  These results support the view that IL-4 may be a risk factor for SM. IL-4 may aggravate the disease by interfering with type 1 T helper cell differentiation or by promoting local inflammation at sites of parasite sequestration.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 906, Faculté de Médecine, Aix-Marseille Université, IFR88, 27 blvd. Jean Moulin, Marseille, France. sandrine.cabantous@univmed.fr
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cabantous
authors.forename: Belco
authors.initials: B
authors.lastname: Poudiougou
authors.forename: Aboubacar A
authors.initials: AA
authors.lastname: Oumar
authors.forename: Abdoualye
authors.initials: A
authors.lastname: Traore
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Barry
authors.forename: Joana
authors.initials: J
authors.lastname: Vitte
authors.forename: Pierre
authors.initials: P
authors.lastname: Bongrand
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marquet
authors.forename: Ogobara
authors.initials: O
authors.lastname: Doumbo
authors.forename: Alain J
authors.initials: AJ
authors.lastname: Dessein
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D015847:Interleukin-4 / Q000097:blood / Q000235:genetics*; D016779:Malaria, Cerebral / Q000235:genetics* / Q000276:immunology; D016778:Malaria, Falciparum / Q000235:genetics* / Q000276:immunology; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C508598:IL4 protein, human; D015847:Interleukin-4