title: Toll-like receptor polymorphisms and cerebral malaria: TLR2 Δ22 polymorphism is associated with protection from cerebral malaria in a case control study.
abstract: BACKGROUND
  In malaria endemic areas, host genetics influence whether a Plasmodium falciparum-infected child develops uncomplicated or severe malaria. TLR2 has been identified as a receptor for P. falciparum-derived glycosylphosphatidylinositol (GPI), and polymorphisms within the TLR2 gene may affect disease pathogenesis. There are two common polymorphisms in the 5' un-translated region (UTR) of TLR2, a 22 base pair deletion in the first unstranslated exon (Δ22), and a GT dinucleotide repeat in the second intron (GTn).
  
  
  METHODS
  These polymorphisms were examined in a Ugandan case control study on children with either cerebral malaria or uncomplicated malaria. Serum cytokine levels were analysed by ELISA, according to genotype and disease status. In vitro TLR2 expression was measured according to genotype.
  
  
  RESULTS
  Both Δ22 and GTn polymorphisms were highly frequent, but only Δ22 heterozygosity was associated with protection from cerebral malaria (OR 0.34, 95% confidence intervals 0.16, 0.73). In vitro, heterozygosity for Δ22 was associated with reduced pam3cys inducible TLR2 expression in human monocyte derived macrophages. In uncomplicated malaria patients, Δ22 homozygosity was associated with elevated serum IL-6 (p = 0.04), and long GT repeat alleles were associated with elevated TNF (p = 0.007).
  
  
  CONCLUSIONS
  Reduced inducible TLR2 expression may lead to attenuated pro-inflammatory responses, a potential mechanism of protection from cerebral malaria present in individuals heterozygous for the TLR2 Δ22 polymorphism.
authors.affiliation: Case Western Reserve University, Wolstein Research Building, 2103 Cornell Rd, Cleveland, OH 44106, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Greene
authors.forename: Nadia
authors.initials: N
authors.lastname: Sam-Agudu
authors.forename: Chandy C
authors.initials: CC
authors.lastname: John
authors.forename: Robert O
authors.initials: RO
authors.lastname: Opoka
authors.forename: Peter A
authors.initials: PA
authors.lastname: Zimmerman
authors.forename: James W
authors.initials: JW
authors.lastname: Kazura
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D060467:Disease Resistance / Q000235:genetics* / Q000276:immunology; D005091:Exons; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D007438:Introns; D016779:Malaria, Cerebral / Q000235:genetics* / Q000276:immunology / Q000469:parasitology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics / Q000276:immunology; D010963:Plasmodium falciparum / Q000502:physiology; D011110:Polymorphism, Genetic / Q000276:immunology*; D017384:Sequence Deletion; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000276:immunology; D014454:Uganda
chemical_list: D015850:Interleukin-6; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2