Haemoglobin C (HbC; β6Glu → Lys) is common in malarious areas of West Africa, especially in Burkina Faso1,2. Conclusive evidence exists on the protective role against severe malaria of haemoglobin S (HbS; β6Glu → Val) heterozygosity3, whereas conflicting results for the HbC trait have been reported4,5,6,7,8,9,10 and no epidemiological data exist on the possible role of the HbCC genotype. In vitro studies suggested that HbCC erythrocytes fail to support the growth of P. falciparum11,12 but HbC homozygotes with high P. falciparum parasitaemias have been observed10. Here we show, in a large case–control study performed in Burkina Faso on 4,348 Mossi subjects, that HbC is associated with a 29% reduction in risk of clinical malaria in HbAC heterozygotes (P = 0.0008) and of 93% in HbCC homozygotes (P = 0.0011). These findings, together with the limited pathology of HbAC and HbCC13 compared to the severely disadvantaged HbSS and HbSC genotypes and the low βS gene frequency in the geographic epicentre of βC1,2,14, support the hypothesis that, in the long term and in the absence of malaria control, HbC would replace HbS in central West Africa.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Livingstone, F. B. Abnormal Hemoglobins in Human Populations (Aldine, Chicago, 1967).
Cavalli Sforza, L. L. & Bodmer, W. F. The Genetics of Human Populations (Freeman, San Francisco, 1971).
Hill, A. V. et al. Common West African HLA antigens are associated with protection from severe malaria. Nature 352, 595–600 (1991).
Thompson, G. R. Significance of Hemoglobin S and C in Ghana. Br. Med. J. 1, 682–685 (1962).
Thompson, G. R. Malaria and stress in relation to Hemoglobins S and C. Br. Med. J. 2, 976–978 (1963).
Ringelhann, B., Hathorn, M. K., Jilly, P., Grant, F. & Parniczky, G. A new look at the protection of hemoglobin AS and AC genotypes against Plasmodium falciparum infection: a census tract approach. Am. J. Hum. Genet. 28, 270–279 (1976).
Molineaux, L. & Gramiccia, G. The Garki Project. Research on the Epidemiology and Control of Malaria in the Sudan Savanna of West Africa (World Health Organization, Geneva, 1980).
Gilles, H. M. et al. Glucose-6-phosphate-dehydrogenase deficiency, sickling, and malaria in African children in South Western Nigeria. Lancet 1, 138–140 (1967).
Guinet, F. et al. A comparison of the incidence of severe malaria in Malian children with normal and C-trait hemoglobin profiles. Acta Trop. 68, 175–182 (1997).
Agarwal, A. et al. Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. Blood 96, 2358–2363 (2000).
Friedman, M. J., Roth, E. F., Nagel, R. L. & Trager, W. The role of hemoglobins C, S, and Nbalt in the inhibition of malaria parasite development in vitro. Am. J. Trop. Med. Hyg. 28, 777–780 (1979).
Olson, J. A. & Nagel, R. L. Synchronized cultures of P. falciparum in abnormal red cells: the mechanism of the inhibition of growth in HbCC cells. Blood 67, 997–1001 (1986).
Smith, E. W. & Krevans, J. R. Clinical manifestations of hemoglobin C disorders. Bull. Johns Hopkins Hosp. 104, 17–43 (1959).
Labie, D., Richin, C., Pagnier, J., Gentilini, M. & Nagel, R. L. Hemoglobins S and C in Upper Volta. Hum. Genet. 65, 300–302 (1984).
Miller, L. H., Mason, S. J., Clyde, D. F. & McGinniss, M. H. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N. Engl. J. Med. 295, 302–304 (1976).
Haldane, J. B. S. The rate of mutation of human genes. Hereditas 35 (suppl.), 267–273 (1949).
Flint, J. et al. High frequencies of alpha-thalassaemia are the result of natural selection by malaria. Nature 321, 744–750 (1986).
Allen, S. J. et al. alpha+-Thalassemia protects children against disease caused by other infections as well as malaria. Proc. Natl Acad. Sci. USA 94, 14736–14741 (1997).
Pasvol, G., Weatherall, D. J. & Wilson, R. J. Cellular mechanism for the protective effect of haemoglobin S against P. falciparum malaria. Nature 274, 701–703 (1978).
Friedman, M. J. Erythrocytic mechanism of sickle cell resistance to malaria. Proc. Natl Acad. Sci. USA 75, 1994–1997 (1978).
Ruwende, C. et al. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature 376, 246–249 (1995).
Hutagalung, R. et al. Influence of hemoglobin E trait on the severity of Falciparum malaria. J. Infect. Dis. 179, 283–286 (1999).
Trabuchet, G. et al. Nucleotide sequence evidence of the unicentric origin of the βC mutation in Africa. Hum. Genet. 87, 597–601 (1991).
Modiano, G., Battistuzzi, G. & Motulsky, A. G. Nonrandom patterns of codon usage and of nucleotide substitutions in human alpha- and beta-globin genes: an evolutionary strategy reducing the rate of mutations with drastic effects? Proc. Natl Acad. Sci. USA 78, 1110–1114 (1981).
Crow, J. F. The origins, patterns and implications of human spontaneous mutation. Nature Rev. Genet. 1, 40–47 (2000).
Sanchaisuriya, K. et al. Molecular characterization of hemoglobin C in Thailand. Am. J. Hematol. 67, 189–193 (2001).
Pagnier, J. et al. Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa. Proc. Natl Acad. Sci. USA 81, 1771–1773 (1984).
Kulozik, A. E. et al. Geographical survey of beta S-globin gene haplotypes: evidence for an independent Asian origin of the sickle-cell mutation. Am. J. Hum. Genet. 39, 239–244 (1986).
Antonarakis, S. E. et al. Evidence for multiple origins of the beta E-globin gene in Southeast Asia. Proc. Natl Acad. Sci. USA 79, 6608–6611 (1982).
Modiano, D. et al. Severe malaria in Burkina Faso: influence of age and transmission level on clinical presentation. Am. J. Trop. Med. Hyg. 59, 539–542 (1998).
We thank all the children in this study, and their parents and teachers, for their understanding and assistance. We thank the paediatric and laboratory staff of the Centre Hospitalier National Yalgado Quédraogo and of the Saint Camille Health Centre of Ouagadougou, Burkina Faso, for technical assistance. This work was based at the Centre National de Recherche et Formation sur le Paludisme of the Ministry of Health of Burkina Faso, co-sponsored by the Italian Cooperation (MAE-DGCS). Financial support was also provided by the European Community and by the Conferenza Episcopale Italiana.
About this article
Cite this article
Modiano, D., Luoni, G., Sirima, B. et al. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414, 305–308 (2001). https://doi.org/10.1038/35104556
Annals of the New York Academy of Sciences (2021)
Human Molecular Genetics (2021)
Molecular Biology and Evolution (2021)
Associations between red blood cell variants and malaria among children and adults from three areas of Uganda: a prospective cohort study
Malaria Journal (2020)