CD36 c.1264 T>G Null Mutation Impairs Acquisition of IgG Antibodies to Plasmodium falciparum MSP1‐₁₉ Antigen and is Associated with Higher Malaria Incidences in Tanzanian Children

Abstract

Polymorphisms in genes that encode crucial signalling molecules have been proposed as factors that influence susceptibility to, and outcome of malaria. We studied the role of a mutation, c.1264 T>G, that causes CD36 deficiency on IgG responses to MSP‐119 antigen and malaria incidence. Children were genotyped for the c.1264 T>G mutation at the beginning of the study using PCR‐RFLP. IgG levels [optical density (OD) readings] and per cent seropositivity to MSP‐119 were determined at baseline by ELISA. Children were followed for 12 months for acquisition of anti‐MSP‐119 IgG antibody and malaria incidence. We observed a significant increase in the production of anti‐MSP‐119 IgG antibody in normal and heterozygous children during the 12 months of follow‐up, but not in homozygous mutants. Normal children had a significantly lower malaria incidence rate compared to other genotypes (χ2 = 115.59; P < 0.01). We conclude that the presence of the c.1264 T>G mutation that leads to CD36 deficiency is closely associated with reduced IgG production and higher malaria incidence. It is most likely that deficiency of CD36 which is known to modulate dendritic cell function suppresses the production of protective IgG antibodies directed to Plasmodium falciparum MSP‐119 antigen, which predisposes to the acquisition of clinical malaria in children.

Genetic determinants of anti-malarial acquired immunity in a large multi-centre study

“…One SNP was found to be marginally associated with antibody levels to merozoite antigens. The SNP in CD36 (rs3211938) on chromosome 7 was associated with a reduction in anti-MSP2 levels using the recessive genetic model, which is consistent with the reduced anti-MSP1 levels observed in individuals recessive homozygous for this SNP in another area of Tanzania [ 68 ]. None of the other loci tested here showed evidence of association with antibodies in this multi-centre analysis with a significance of P < 10 −4 .…”

The Host Genetic Diversity in Malaria Infection

“…However, in contrast to ICAM-1, this molecule is not expressed on the endothelial cells of brain capillaries [198]. CD36 serves as a receptor for several ligands, including low-density lipoprotein cholesterol (LDL-C), collagen, thrombospodin, and anionic phospholipids and participates in macrophage fusion induced through IL-4 [199]. Mutations in the CD36 receptor gene have been associated with protection against or susceptibility to severe forms of malaria.…”

“…Mutations in the CD36 receptor gene have been associated with protection against or susceptibility to severe forms of malaria. The CD36 deficiency might be induced through the two SNPs in the CD36 gene (T1264G in exon 10, rs3211938 and G1439C in exon 12, no rs designation available), which encode the truncated proteins that were expressed at high frequency in patients with severe malaria in Gambian, Tanzanian, and Kenyan patients [199–201]. This association was confirmed in a study in India, showing an association of the presence of the mutant allele in heterozygous individuals (1264T>G in exon 10) with protection against severe malaria [202].…”

A tale of agriculturalists and hunter‐gatherers: Exploring the thrifty genotype hypothesis in native South Americans

“…Furthermore, CD36 encodes the platelet glycoprotein 4, an adhesion molecule involved in the interaction between parasite ligands and host receptors. Most P. falciparum antigens are known to bind CD36 ; thus, mutations in the CD36 gene can influence malaria outcome (Aitman et al, ; Cserti‐Gazdewich et al, ; Kajeguka et al, ). The higher frequency of CD36 TT in hunter‐gatherer populations, therefore, may be also due to immunologic selective pressure, a possibility not mutually exclusive with TGH, since CD36 TT genotype was also associated with larger waist circumferences and body mass indices in some populations (Heni et al, ).…”