CR1 density polymorphism on erythrocytes of falciparum malaria patients in Thailand.

Abstract

Abstract. Complement receptor type 1 (CR1) on erythrocytes shows an inherited numerical polymorphism which correlates with a HindIII-RFLP (restriction fragment length polymorphism) of the CR1 gene in various populations. To investigate the relationship between CR1 density polymorphism and disease severity, we typed 185 Thai patients with acute falciparum malaria (55 severe and 130 uncomplicated) for their genotypes of this polymorphism. The level of expression of erythrocyte CR1 from 42 randomly selected patients was measured by enzyme-linked immunosorbent assay (ELISA). We observed a significantly higher frequency of homozygotes of the CR1 low density allele (LL) among the severe group as compared to the uncomplicated group (P ϭ 0.005). CR1 expression on erythrocytes from patients with the LL genotype was significantly lower than homozygotes with the high density allele (HH) (P Ͻ 0.0001) and heterozygotes (HL) (P ϭ 0.013). The results suggest that a genetically-determined low CR1 density on erythrocytes may be a risk factor for developing a more severe form of malaria in Thai subjects.

Mechanisms of genetically-based resistance to malaria

“…However, unexpected and contradictory results have been obtained. Severe malaria was thus associated with low-level CR1 genotype and high-level genotype with rosette formation in a study carried out by Nagayasu et al (2001). Thathy et al (2005) have shown that low-CR1 phenotypes confer protection against cerebral malaria but not against malaria-associated anemia in Kenyan children.…”

A human complement receptor 1 polymorphism that reducesPlasmodium falciparumrosetting confers protection against severe malaria

“…It is unclear whether the difference between the levels of protection provided by the HL and LL genotypes is genuine, and a larger sample size would be required to resolve this issue. The only previous small study of CR1 polymorphisms and malaria suggested that the LL genotype is a risk factor for severe malaria in Thai adults (36). In Southeast Asia, severe malaria in characterized mainly by metabolic disturbances and multiorgan failure (37) rather than by severe anemia and cerebral malaria, which occur commonly in children in PNG (38).…”

Evidence for malaria selection of a CR1 haplotype in Sardinia

“…15 This allele has been associated with a multifold reduction of the level of CR1 in multiple studies of subjects with European ancestry, [15][16][17][18] and also in South Asian and East Asian population groups. 19,20 Previous studies in Europeans have also found that this haplotype also contains the rs3738467 T allele (Gln981His), an allele that is associated with decreased CR1 in European, East Asian and Papua New Guineans. 15,19,21 Other studies have also identified additional amino acid variants, including the Ile1574Val (rs669117 G allele), as part of this haplotype.…”

“…19,20 Previous studies in Europeans have also found that this haplotype also contains the rs3738467 T allele (Gln981His), an allele that is associated with decreased CR1 in European, East Asian and Papua New Guineans. 15,19,21 Other studies have also identified additional amino acid variants, including the Ile1574Val (rs669117 G allele), as part of this haplotype. 15 CR1 has also been shown to have a direct interaction with the Plasmodium falciparum erythrocyte membrane protein 1 that is a major adhesion molecule expressed on malarial infected erythrocytes, 22 and many studies have suggested an important role for CR1 in malarial infection and pathogenesis.…”