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.

John M Ong'Echa,Douglas J Perkins,John M Vulule,Gregory C Davenport,Stephen Konah,Samuel B Anyona,Prakasha M Kempaiah,Evans O Raballah,Collins Ouma,Tom Were,James B Hittner

doi:10.1186/1471-2156-12-69

Abstract

BackgroundPlasmodium 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<6.0g/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.ResultsMultivariate 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.ConclusionThe 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.

Highlights

Plasmodium falciparum malaria remains a leading cause of morbidity and mortality among African children
Since severe anaemia is the primary manifestation of severe malaria in holoendemic P. falciparum transmission regions, with cerebral malaria being a rare occurrence, this study examined the role of rs3212227 in conditioning the development of severe anaemia and as such, it remains to be determined if results obtained here are applicable to areas with differing endemicities of malaria in which individuals develop severe disease manifestations apart from severe anaemia
Our previous studies showing that reduced IL-12p70 production is associated with enhanced severity of malaria in African children [8,34] illustrate the importance of IL-12 in human malaria as well. Consistent with these investigations, the current study demonstrated that children with acute malaria that develop severe malarial anaemia (SMA) have significantly lower circulating IL-12p40/p70 levels than children that fail to progress to severe anaemia

Summary

Introduction

Plasmodium falciparum malaria remains a leading cause of morbidity and mortality among African children. 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). Our previous studies in Gabonese and Kenyan children with malaria showed that suppression of circulating IL-12 was associated with decreased Hb concentrations [8,9]. These results are consistent with studies in murine models showing that IL-12 protects against malaria by enhancing erythropoiesis and, thereby, reducing severe anaemia [10]. Unlike a number of other cytokines that show divergent results in differing species, the association between reduced IL-12 production and enhanced malaria disease severity appears conserved across the phylogenetic spectrum

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