Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting

Abstract

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.

Fig. 1.

ABO blood group frequencies in cases and controls and the effect of host ABO blood group on P. falciparum rosetting in Mali. (A) Distribution of ABO blood group frequencies in severe malaria cases and matched uncomplicated malaria controls and healthy controls (n = 124 triplets). Percentages are shown within each section of the pie. (B) Distribution of ABO blood group frequencies in nonsevere hyperparasitemia cases and matched uncomplicated malaria controls and healthy controls (n = 65 triplets). Percentages are shown within each section of the pie. (C) Box plot showing the effect of host ABO blood group on rosetting in Malian P. falciparum isolates (group A, n = 51; group AB, n = 12; group B, n = 66; group O, n = 76). Boxes indicate median (central line) and interquartile range. The 90th percentile is shown by the error bar, and points beyond the 90th percentile are shown as circles. Rosetting is significantly lower in isolates from blood group O patients compared with the non-O blood groups (P = 0.003, Kruskal–Wallis test).

Fig. 2.

Rosetting and severe malaria in Mali in relation to ABO blood group. The distributions of rosette frequencies in patients with nonsevere hyperparasitemia (hyp), severe malaria (severe), and uncomplicated malaria (uncomp) are shown as box plots (as in Fig. 1) for each ABO blood group type. High levels of rosetting were seen most frequently in severe malaria isolates in groups A, B, and AB, but not in group O (Kruskal–Wallis test; P value shown in parentheses above each graph). Numbers in each category are as follows: group A (hyp, 8; severe, 27; and uncomp, 16); group AB (hyp, 2; severe, 4; and uncomp, 5); group B (hyp, 11; severe, 29; and uncomp, 25); group O (hyp, 17; severe, 15; and uncomp, 43).