Promoter Polymorphism of the Anion-Exchange Protein 1 Associated with Severe Malarial Anemia and Fatality

Abstract

The anion-exchange protein 1 (AE1 or band 3) is involved in the erythrocyte invasion of the malaria parasite Plasmodium falciparum, the adhesion of infected erythrocytes to endothelial cells, and the regulation of acidbase homeostasis, which is a critical factor for human survival in severe malaria. A variant of the AE1 gene promoter 512 base pairs (bp) distant from the transcription start site and 5699 bp from the translation start codon (AE1 5699TrC) has been shown to be highly frequent in a population from the Ashanti region, Ghana. In a matched-pair case-control study (736 pairs), children heterozygous for the mutation (AE1 5699CT) had an increased risk of severe malarial anemia (odds ratio [OR], 1.45 [95% confidenc interval {CI}, 1.05–2.01]; P ! .03). In children who developed this complication, carriers of the mutation AE1 5699C had a higher fatality rate than those with the genotype AE1 5699TT (relative risk, 7.1 [95% CI, 1.0–52.8]). Moreover, in children with cerebral malaria, AE1 5699C was positively associated with a distinctive metabolic acidosis (P ! .002), and results of luciferase assays showed higher transcriptional activity of the AE1 5699C allele. These results demonstrate that the AE1 promoter allele might influenc the infection phenotype and the risk of fatal outcome in children with severe malaria. In this regard, a crucial role of the AE1 protein in malaria is emphasized.