Hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack

Genetic predisposition to malaria has been shown by epidemiological, case–control and linkage studies. In particular, case–control studies have recently shown association between hemoglobin C and resistance to severe malaria in Mali and to clinical malaria in Burkina Faso. In a longitudinal study of families living in an endemic area, we investigated whether hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack. We surveyed 256 individuals (71 parents and 185 sibs) from 53 families during 2 years. Hemoglobin C carriers had less frequent malaria attacks than AA individuals within the same age group (P ¼ 0.01). Since age correlated with malaria attack and parasitemia (P < 0.0001), we took age into account in association analyses. We performed combined linkage and association analyses, which avoid biases due to population structure. Using multi-allelic tests, we evidenced association between hemoglobin genotype and phenotypes related to malarial infection and disease (P < 0.001). We further analyzed individual hemoglobin alleles and detected negative association between hemoglobin C and malaria attack (P ¼ 0.00013). Analyses that took into account confounding factors confirmed the negative association of hemoglobin C with malaria attack (P ¼ 0.0074) and evidenced a negative correlation between hemoglobin C and parasitemia (P ¼ 0.0009). These associations indicate that hemoglobin C reduces parasitemia and confers protection against mild malaria attack.