FCGR2A functional genetic variant associated with susceptibility to severe malarial anaemia in Ghanaian children.

BACKGROUND

Severe malarial anaemia is a major cause of mortality from malaria. Although of enormous relevance, its pathogenesis is largely unknown. Interestingly, the extent of anaemia greatly exceeds the loss of erythrocytes due to direct destruction by the pathogen Plasmodium falciparum. Immune response against the parasite is partially mediated through the Fc receptor for immunoglobulin (Ig) G IIa (FcgammaRIIa, CD32). The presence of an arginine instead of a histidine residue at amino acid position 131 (H131R) in the extracellular domain of FcgammaRIIa reduces the affinity of the receptor for IgG(2) and IgG(3) isotypes but increases the binding activity for C reactive protein (CRP).

METHODS

In Ghana, West Africa, 2504 children with severe malaria and 2027 matched healthy controls were studied for the FcgammaRIIa(H131R) polymorphism in order to ascertain its influence on major manifestations of the disease. The study group included patients with partly overlapping symptoms of severe malaria, among them 1591 cases with severe anaemia, 562 cases with cerebral malaria, and 497 cases with other malaria complications.

RESULTS

Analyses of the genotype distributions indicated that, under a recessive model, FcgammaRIIa(131RR) was positively associated with severe malaria collectively (OR 1.20, 95% CI 1.05 to 1.38; p=0.007, p(corrected)=0.021) and, after stratification for phenotypes, with severe anaemia (OR 1.33, 95% CI 1.13 to 1.57; p=0.001, p(corrected)=0.009), but not with cerebral malaria (OR 1.04, 95% CI 0.82 to 1.33; p=0.733) or other malaria complications (OR 1.03, 95% CI 0.78 to 1.37; p=0.827). No association was found with levels of parasitaemia.

CONCLUSION

The positive association with a CRP binding variant of FcgammaRIIa supports evidence for a role of CRP mediated defence mechanisms in the pathogenesis of severe malarial anaemia.