title: 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.
authors.affiliation: Research Group for Infection Epidemiology, Bernhard Nocht Institute for Tropical Medicine, D-20359 Hamburg, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: von Kalckreuth
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Evans
authors.forename: Christian
authors.initials: C
authors.lastname: Timmann
authors.forename: Daniela
authors.initials: D
authors.lastname: Kuhn
authors.forename: Tsiri
authors.initials: T
authors.lastname: Agbenyega
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Horstmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: May
mesh_terms: D000293:Adolescent; D000740:Anemia / Q000235:genetics / Q000401:mortality* / Q000469:parasitology / Q000503:physiopathology*; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics*; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000235:genetics / Q000401:mortality / Q000469:parasitology / Q000503:physiopathology*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012720:Severity of Illness Index
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte