A functional single-nucleotide polymorphism in the CR1 promoter region contributes to protection against cerebral malaria.

BACKGROUND Although the level of erythrocyte complement receptor type 1 (E-CR1) expression in patients with malaria has been extensively studied, whether the level of expression of E-CR1 is associated with severe malaria remains controversial. The present study examined a possible association of polymorphisms in the CR1 gene with the severity of malaria, and it evaluated the influence of the associated polymorphism on expression of E-CR1. METHODS Seventeen single-nucleotide polymorphisms in CR1 were genotyped in 477 Thai patients who had Plasmodium falciparum malaria (203 had mild malaria, 165 had noncerebral severe malaria, and 109 had cerebral malaria). The E-CR1 expression level was measured by flow cytometry in 24 healthy Thai subjects. RESULTS The T allele of the reference single-nucleotide polymorphism rs9429942 in the CR1 promoter region was strongly associated with protection against cerebral malaria (2.2% of patients with mild malaria vs. 7.8% of patients with cerebral malaria; P = .0009; Bonferroni-adjusted Pc = .0306. The E-CR1 expression level was significantly higher in individuals with the TT genotype of rs9429942 than in individuals with the TC genotype of rs9429942 (P = .0282). CONCLUSIONS We identified a CR1 promoter allele, associated with higher E-CR1 expression, that conferred protection against cerebral malaria. Previous studies have shown that the rate of clearance of immune complexes (ICs) from the circulation is related to the E-CR1 level. These results lead to the hypothesis that the clearance of ICs regulated by E-CR1 therefore plays a crucial role in the pathogenesis of cerebral malaria.