title: Polymorphic variability in the 3' untranslated region (UTR) of IL12B is associated with susceptibility to severe anaemia in Kenyan children with acute Plasmodium falciparum malaria.
abstract: BACKGROUND
  Plasmodium falciparum malaria remains a leading cause of morbidity and mortality among African children. Innate immunity provides the first line of defence against P. falciparum infections, particularly in young children that lack naturally-acquired malarial immunity, such as the population examined here. Consistent with the fact that elevated interleukin (IL)-12 is an important component of the innate immune response that provides protective immunity against malaria, we have previously shown that suppression of IL-12 in African children is associated with the development of severe malarial anaemia (SMA). Since the role of IL12B variants in conditioning susceptibility to SMA remains largely unexplored, the association between a single nucleotide polymorphism (1188A→C, rs3212227), SMA (Hb<6.0 g/dL), circulating IL-12p40/p70 levels, and longitudinal clinical outcomes in Kenyan children (n = 756) residing in a holoendemic falciparum malaria transmission area were investigated.
  
  
  RESULTS
  Multivariate logistic regression analysis in children with acute malaria (n = 544) demonstrated that carriers of the C allele had increased susceptibility to SMA (CC: OR, 1.674; 95% CI, 1.006-2.673; P = 0.047, and AC: OR, 1.410; 95% CI, 0.953-2.087; P = 0.086) relative to wild type (AA). Although children with SMA had lower IL-12p40/p70 levels than the non-SMA group (P = 0.037), levels did not differ significantly according to genotype. Longitudinal analyses in the entire cohort (n = 756) failed to show any significant relationships between rs3212227 genotypes and either susceptibility to SMA or all-cause mortality throughout the three year follow-up.
  
  
  CONCLUSIONS
  The rs3212227 is a marker of susceptibility to SMA in children with acute disease, but does not appear to mediate functional changes in IL-12 production or longitudinal outcomes during the acquisition of naturally-acquired malarial immunity.
authors.affiliation: Centre for Global Health Research, University of New Mexico Laboratories of Parasitic and Viral Diseases, Kenya Medical Research Institute, Kisumu, Kenya.
authors.forename: John M
authors.initials: JM
authors.lastname: Ong'echa
authors.forename: Evans O
authors.initials: EO
authors.lastname: Raballah
authors.forename: Prakasha M
authors.initials: PM
authors.lastname: Kempaiah
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Anyona
authors.forename: Tom
authors.initials: T
authors.lastname: Were
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Davenport
authors.forename: Stephen
authors.initials: S
authors.lastname: Konah
authors.forename: John M
authors.initials: JM
authors.lastname: Vulule
authors.forename: Collins
authors.initials: C
authors.lastname: Ouma
authors.forename: James B
authors.initials: JB
authors.lastname: Hittner
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Perkins
mesh_terms: D020413:3' Untranslated Regions; D000740:Anemia / Q000150:complications / Q000235:genetics* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D053762:Interleukin-12 Subunit p40 / Q000235:genetics*; D007630:Kenya; D008137:Longitudinal Studies; D016778:Malaria, Falciparum / Q000150:complications* / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D020413:3' Untranslated Regions; C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40