A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria - PubMed (original) (raw)

A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria

Ian A Cockburn et al. Proc Natl Acad Sci U S A. 2004.

Abstract

Parasitized red blood cells (RBCs) from children suffering from severe malaria often adhere to complement receptor 1 (CR1) on uninfected RBCs to form clumps of cells known as "rosettes." Despite a well documented association between rosetting and severe malaria, it is controversial whether rosetting is a cause or a correlate of parasite virulence. CR1-deficient RBC show greatly reduced rosetting; therefore, we hypothesized that, if rosetting is a direct cause of malaria pathology, CR1-deficient individuals should be protected against severe disease. In this study, we show that RBC CR1 deficiency occurs in up to 80% of healthy individuals from the malaria-endemic regions of Papua New Guinea. This RBC CR1 deficiency is associated with polymorphisms in the CR1 gene and, unexpectedly, with alpha-thalassemia, a common genetic disorder in Melanesian populations. Analysis of a case-control study demonstrated that the CR1 polymorphisms and alpha-thalassemia independently confer protection against severe malaria. We have therefore identified CR1 as a new malaria resistance gene and provided compelling evidence that rosetting is an important parasite virulence phenotype that should be a target for drug and vaccine development.

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Figures

Fig. 1.

Fig. 1.

RBC CR1 deficiency is common in Melanesians and is associated with SNPs in the CR1 gene. (a) RBC CR1 levels in Edinburgh (United Kingdom), Madang (PNG), and New Ireland (PNG). Each point represents the mean RBC CR1 level of a single individual in molecules per cell. SD, standard deviation. (b_–_d) RBC CR1 levels in relation to CR1 genotype based on typing at the n3650 polymorphism in exon 22. H, high-expression allele; L, low-expression allele; na, not applicable.

Fig. 2.

Fig. 2.

RBC CR1 deficiency in Melanesians is associated with α-thalassemia. (a and b) RBC CR1 level in relation to α-thalassemia genotype. Thalassemia genotypes are the following: -α/αα, heterozygotes for the -α4.2 deletion (32); -α/-α, homozygotes for the -α4.2 deletion; and αα/αα, normal α-globin gene structure. Only one individual carried the -α3.7 deletion (32); therefore, this case was excluded from the analysis. (c) The effect of α-thalassemia and CR1 exon 22 genotype on RBC CR1 level are independent of each other. The mean CR1 level for the Madang population subdivided by CR1 genotype (n3650 polymorphism) and α-thalassemia (-α4.2 deletion) is shown, and standard errors are indicated. The HH/normal α-globin genotype was not represented.

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