Apolipoprotein E is a monomeric
protein secreted by the liver and responsible for the transport of plasma
cholesterol and
triglycerides. The
APOE gene encodes 3
isoforms Ɛ4, Ɛ3 and Ɛ2 with
APOE Ɛ4 associated with higher plasma
cholesterol levels and increased pathogenesis in several
infectious diseases (HIV, HSV). Given that
cholesterol is an important nutrient for
malaria parasites, we examined whether
APOE Ɛ4 was a risk factor for
Plasmodium infection, in terms of prevalence or parasite density. A cross sectional survey was performed in 508 children aged 1 to 12 years in Gabon during the wet season. Children were screened for Plasmodium spp.
infection,
APOE and
hemoglobin S (HbS) polymorphisms. Median parasite densities were significantly higher in
APOE Ɛ4 children for Plasmodium spp. densities compared to non-
APOE Ɛ4 children. When stratified for HbS polymorphisms, median Plasmodium spp. densities were significantly higher in
HbAA children if they had an
APOE Ɛ4 allele compared to those without an
APOE Ɛ4 allele. When considering non-
APOE Ɛ4 children, there was no quantitative reduction of Plasmodium spp. parasite densities for HbAS compared to
HbAA phenotypes. No influence of
APOE Ɛ4 on successful Plasmodium liver cell invasion was detected by multiplicity of
infection. These results show that the
APOE Ɛ4 allele is associated with higher median
malaria parasite densities in children likely due to the importance of
cholesterol availability to parasite growth and replication. Results suggest an epistatic interaction between
APOE and HbS genes such that
sickle cell trait only had an effect on parasite density in
APOE Ɛ4 children. This suggests a linked pathway of regulation of parasite density involving expression of these genes. These findings have significance for understanding host determinants of regulation of
malaria parasite density, the design of clinical trials as well as studies of
co-infection with Plasmodium and other pathogens.