Haemoglobin variant gives strong protection against malaria



A genetic variation of haemoglobin, the oxygen-carrying protein found in red blood cells, can almost completely abolish the risk of falciparum malaria, the most lethal form of the disease, according to a study in West Africa reported by African and Italian researchers in the 15 November issue of Nature. Having two copies of the gene for the variant, called haemoglobin C, provides "almost complete protection" against the disease, according to malaria researcher and study team leader Dr Mario Coluzzi of the University of Rome La Sapienza.

Moreover, haemoglobin C comes with few unhealthy strings attached. Mild anaemia and, in some adults, gallstones are the only adverse effects. "Compared to all other red blood cell mutations that protect against malaria, haemoglobin C is not associated with serious health problems," says Dr David Modiano, lead author of the study.

Scientists have known for years that another version of the haemoglobin gene, haemoglobin S, shields against malaria by crippling the red blood cells that malaria parasites need to survive. The abnormal haemoglobin distorts red blood cells into a sickle shape, and these misshapen cells along with any parasites they contain are destroyed by the spleen. But with haemoglobin S, malaria protection comes at a cost. People with two copies of the haemoglobin S gene often develop potentially lethal sickle-cell anaemia.

Earlier work by other research teams, including an epidemiological study in Mali and laboratory experiments on parasite proliferation, had suggested a link between haemoglobin C and malaria resistance, but the results were inconclusive. The Rome team confirmed the protective effect of haemoglobin C by studying the blood of 4348 children of the Mossi ethnic group in Ouagadougou, Burkina Faso. The majority of the participants were healthy, but 835 of them had malaria caused by the parasite Plasmodium falciparum. The scientists determined which forms of the haemoglobin gene each child had inherited.

When the researchers compared the genetic data between the healthy and sick children, they found far fewer haemoglobin C genes among the sick patients. Statistical analysis predicted that 14 of the sick children would have two copies of the haemoglobin C gene if the variant offered no protection against the disease. Instead, only one sick child had a double dose of the gene. Based on their findings, the scientists calculate that having a haemoglobin C gene paired with a normal haemoglobin gene reduces the risk of malaria by 29% compared to having two normal haemoglobin genes. Having two copies of the haemoglobin C gene reduces the risk by a huge 93%. That is slightly more protective than the 73% risk reduction experienced by people having a normal haemoglobin gene paired with a haemoglobin S gene (HbAS genotype), and certainly more protective than the approximately 67% protection afforded by having two copies of the haemoglobin S gene (HbSS), although the lethality of that genotype clearly offsets its protective effect.

Modiano and his colleagues are currently conducting a study of more than 5000 people, children and adults, in Burkina Faso to find out whether haemoglobin C merely keeps the disease in check or if it totally blocks infection. How the haemoglobin could accomplish either task remains a mystery. The abnormal protein might produce slight changes in the way antigens are exposed on the surface of red blood cells, says Modiano. Determining how haemoglobin C fends off malaria might guide the development of vaccines and better treatments that safely mimic the mechanism of action involved.

Charlene Crabb, Paris, France

World Health Organization Genebra - Genebra - Switzerland
E-mail: bulletin@who.int