Every year, malaria affects half a billion people and kills up to 3 million of them. For ∼10,000 years, malaria has put the human genome under considerable selective pressure to evolve natural ways of resistance — the sickle cell haemoglobin (HbS) variant being a classic example. But other haemoglobin variants have been described and some, such as haemoglobin C (HbC), have been implicated in resistance to malaria. Until recently, the link has been tenuous, but Modiano and colleagues now provide conclusive evidence that, when homozygous, HbC confers substantial resistance to this devastating disease.

HbC is a common West African haemoglobin variant in which glutamic acid at position 6 has been mutated to lysine but, unlike the HbS mutation, this substitution does not affect the molecule's affinity for oxygen. Following inconclusive reports about the role of HbC in resistance to malaria, Modiano et al. re-examined the issue by looking at HbC frequency among 4,348 children in West African Burkina Faso. The authors found that HbC frequency was markedly reduced among 835 children who had been hospitalized with malaria; moreover, there was only one HbC homozygous individual among them. HbC frequency in the sick population indicates that, when heterozygous, HbC could account for a 29% reduction in the relative risk of clinical malaria and 93% when homozygous — compared to 70% reduction among HbS carriers.

Given the very high level of protection that HbC bestows on homozygous individuals, and the lack of obvious adverse effects among HbC carriers, Modiano and colleagues suggest that the allele is likely to rise in frequency among Africans, and will perhaps even replace the HbS variant in Africa. But because its protective effects mainly manifest themselves in homozygotes, the spread of the allele is likely to be slow. It will also be useful to understand the mechanism behind the protection afforded by HbC — this might provide some new insight into the biology of malaria and potentially lead to new treatments.