Malaria has been a major selective force on the human population, and several erythrocyte polymorphisms have evolved that confer resistance to severe
malaria. Plasmodium falciparum rosetting, a parasite virulence phenotype associated with severe
malaria, is reduced in
blood group O erythrocytes compared with groups A, B, and AB, but the contribution of the
ABO blood group system to protection against severe
malaria has received little attention. We hypothesized that
blood group O may confer resistance to severe
falciparum malaria through the mechanism of reduced rosetting. In a matched case-control study of 567 Malian children, we found that group O was present in only 21% of severe
malaria cases compared with 44-45% of uncomplicated
malaria controls and healthy controls. Group O was associated with a 66% reduction in the odds of developing severe
malaria compared with the non-O
blood groups (odds ratio 0.34, 95% confidence interval 0.19-0.61, P < 0.0005, severe cases versus uncomplicated
malaria controls). In the same sample set, P. falciparum rosetting was reduced in parasite isolates from group O children compared with isolates from the non-O
blood groups (P = 0.003, Kruskal-Wallis test). Statistical analysis indicated a significant interaction between host
ABO blood group and parasite rosette frequency that supports the hypothesis that the protective effect of group O operates through the mechanism of reduced P. falciparum rosetting. This work provides insights into
malaria pathogenesis and suggests that the selective pressure imposed by
malaria may contribute to the variable global distribution of ABO
blood groups in the human population.