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 (FcγRIIa, CD32). The presence of an arginine instead of a histidine residue at amino acid position 131 (H131R) in the extracellular domain of FcγRIIa reduces the affinity of the receptor for IgG₂ and IgG₃ 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 FcγRIIa^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, FcγRIIa^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 FcγRIIa supports evidence for a role of CRP mediated defence mechanisms in the pathogenesis of severe malarial anaemia.