title: Genetic evidence of regulatory gene variants of the STAT6, IL10R and FOXP3 locus as a susceptibility factor in uncomplicated malaria and parasitaemia in Congolese children.
abstract: BACKGROUND
  Regulatory T cells (Tregs) are a subset of T cells that play an important role in modulating T effector responses during infectious challenges. The aim of this study was to evaluate possible associations between regulatory gene polymorphisms and the risk of uncomplicated malaria and the control of Plasmodium falciparum parasite density levels.
  
  
  METHODS
  Twelve regulatory single nucleotide polymorphisms (SNPs) in the promoter regions of FOXP3 (ss270137548, rs11091253), IL10RA (rs56356146, rs7925112), IL10RB (rs8178433, rs8178435, rs999788), STAT6 (rs3024941, rs3024943, rs3024944) and TNFRSF18 (ss2080581728, rs3753344) were genotyped in a cohort of Congolese children. Studied subjects were followed up (passively) during one year. The children who experienced one or several clinical episodes were genotyped as "uncomplicated malaria" group (n=179) and those children who did not experience any episode were genotyped as "asymptomatic children" group (n=138).
  
  
  RESULTS
  The prevalence of rs3024944CC genotype of STAT6 was significantly higher in the group of asymptomatic children compared to that of uncomplicated malaria (P=0.003). Similarly, the minor allele rs3024944C was more prevalent in the group of asymptomatic children (P=0.019). Two novel SNPs were observed including -163T/G (ss491228441) in IL10RA gene and -163C/T (ss491228440) in TNFRSF18 gene. The genotype ss491228441TT and the minor allele ss491228441G of the IL10RA were more frequent in the group of asymptomatic children (P=0.006 and P=0.007, respectively). The genotype rs11091253CT of the FOXP3 was associated with high parasite density levels. In addition, a new promoter IL10RA variant (ss491228441) contributes to shield against mild malaria.
  
  
  CONCLUSIONS
  The study indicated that the STAT6 promoter polymorphism rs3024944 was associated with uncomplicated malaria, whereas the FOXP3 promoter variant rs11091253 was associated with significant P. falciparum parasitaemia levels. These genetic data may contribute to the understanding of molecular mechanisms that regulate immune response to P. falciparum infections.
authors.affiliation: Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Koukouikila-Koussounda
authors.forename: Francine
authors.initials: F
authors.lastname: Ntoumi
authors.forename: Mathieu
authors.initials: M
authors.lastname: Ndounga
authors.forename: Hoang V
authors.initials: HV
authors.lastname: Tong
authors.forename: Ange-Antoine
authors.initials: AA
authors.lastname: Abena
authors.forename: Thirumalaisamy P
authors.initials: TP
authors.lastname: Velavan
mesh_terms: D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003223:Congo; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics*; D016778:Malaria, Falciparum / Q000235:genetics* / Q000276:immunology; D008297:Male; D018512:Parasitemia / Q000235:genetics* / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D050800:STAT6 Transcription Factor / Q000235:genetics*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053709:Interleukin-10 Receptor alpha Subunit; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human