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 acid-base 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(-5699T-->C)) 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% confidence 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 influence 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.

Single Particle Electron Microscopy Analysis of the Bovine Anion Exchanger 1 Reveals a Flexible Linker Connecting the Cytoplasmic and Membrane Domains

“…AE1 also participates in the formation of a senescent cell antigen in aged erythrocytes [7]. The structure of AE1 is likely altered in several pathological conditions including thalassemia, sickle cell anemia, and red cells harboring the malaria parasite Plasmodium falciparum [8], [9], [10], [11], [12], [13]. In the erythrocyte membrane, AE1 forms oligomers that are predominantly dimers and tetramers.…”

Blood Groups in Infection and Host Susceptibility

“…Finally, one study reported a link between severe P. falciparum infection in children and a polymorphism in the AE1 promoter (540). The polymorphism is T¡C at nucleotide Ϫ5699 (SLC4A1 ϪT5699C ), ϳ500 bp upstream of the transcription start site.…”

“…Although allelic variants were equally represented (50% frequency) in the population, the prevalence of the SLC4A1 Ϫ5699C allele was increased among fatal cases, with the highest relative risk of death being observed for homozygous patients. In luciferase assays, the SLC4A1 Ϫ5669C variant displayed 18 to 27% higher promoter activity in K562 erythroleukemia cells (540). It is unknown whether increased promoter activity is associated with higher AE1 expression levels or altered red cell deformability.…”

Anemia in Kassala Area Eastern Sudan

“…Attachment of malaria parasite antigen to the non parasitized red cell leads to their haemolysis via a complement-mediated immune response. This explains the positive direct Comb's test found sometimes during malaria infection 8,9 . Splenomegaly in malaria contributes to anemia either by raised plasma volume, sequestration or as a result of hypersplenism resulting from tropical splenomegaly syndrome 10 .…”