CR1 Knops blood group alleles are not associated with severe malaria in the Gambia

The Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens SI1/SI2 and McCa/McCb, we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with SI:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for SI 2 (0.800, 1365/1706) and McCb (0.385, 658/1706) were observed. Further, when compared to the SI 1/McCa allele observed in all populations, the African SI 2/McCb allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e. = 1.77, P-value < 0.05). Given the role of CR1 in host defense, our findings suggest that SI 2 and McCb have arisen to confer a selective advantage against infectious disease that, in view of these case - control study data, was not solely Plasmodium falciparum malaria. Factors underlying the lack of association between SI 2 and McCb with severe malaria may involve variation in CR1 expression levels. © 2003 Nature Publishing Group All rights reserved.