Background: Severe malarial anemia is a major cause of mortality from malaria. Although of enormous relevance, its pathogenesis is largely unknown. Interestingly, the extent of anemia 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 histdine 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 FcγRIIaH131R 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 anemia, 562 cases with cerebral malaria and 497 cases with other malaria complications.
Results: Analyses of the genotype distributions indicated that, under a recessive model, FcγRIIa131RR was positively associated with severe malaria collectively (odds ratio [OR], 1.20; 95% confidence interval [CI], 1.05-1.38; p=0.007, pcorrected=0.021) and, after stratification for phenotypes, with severe anemia (OR, 1.33; CI, 1.13-1.57; p=0.001, pcorrected=0.009) but not with cerebral malaria (OR, 1.04; CI, 0.82-1.33; p=0.733) or other malaria complications (OR, 1.03; CI, 0.78-1.37; p=0.827). No association was found with levels of parasitemia.
Conclusion: The positive association with a CRP-binding variant of FcγRIIa supports evidence for a role of CRP-mediated defense mechanisms in the pathogenesis of severe malarial anemia.
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