Malaria deaths are linked to genetic traits

PEOPLE may die from infectious disease not because the infection is particularly virulent, but because their own genes have marked them down.

According to Dr Bill McGuire, of the Institute of Molecular Medicine in Oxford, children living in The Gambia, West Africa, who have inherited a particular combination of genes from their parents are seven times more likely to die after infection with malaria than children with different genes. Paradoxically, the 'risky' genes are responsible for producing higher levels of a molecule which normally stimulates the immune system's defences against infection.

Susceptibility to tuberculosis and leprosy may also be influenced in the same way, Dr McGuire said. Following publication of the malaria study in today's issue of the scientific journal Nature, the researchers will now be tracking the genetic response to these diseases.

Almost 2 million people die each year from malaria, usually from the severest form which affects the brain and is known as cerebral malaria. About half a million children die of cerebral malaria each year in Africa alone.

The team of researchers, led by Dr Dominic Kwiatkowski also of the institute, conducted a case- controlled study in the late 1980s of more than 1,000 children in The Gambia, where the UK's Medical Research Council runs an internationally renowned laboratory. Dr McGuire said: 'Most children in The Gambia suffer malaria infection at some time in the year, but only a small fraction of them die. The most common fatal complication is cerebral malaria.'

When the malaria parasites invade the body, they trigger the infected person to make molecules which activate the immune system but which also cause many of the symptoms of infection such as aches and fever. Particularly important in malaria is Tumor Necrosis Factor (TNF) which helps fight the infection by causing the high temperatures - the raging fevers familiarly associated with malaria. These high temperatures damage the parasites.

But according to Dr McGuire, TNF also makes the inner lining of the blood vessels sticky to blood cells laden with malaria parasites. In cerebral malaria, the blood supply to the brain may be choked off because the blood vessels supplying the brain get congested.

Last year, researchers in Sheffield announced that they had discovered two different variants of the gene responsible for producing TNF. One variant could lead to excessive production of TNF. This sent Dr Kwiatkowski and his colleagues back to their deep freezes where they had stored DNA, taken in the form of blood samples from Gambian children.

The reseachers found that a child who inherited two copies of the high-production variant - one each from their mother and father - was seven times more likely to develop cerebral malaria than those who had inherited just one copy or none at all.

'Normally, the TNF response is a good thing, to activate the immune system,' Dr McGuire said. However, having an overactive immune system may be a bad thing. 'TNF probably contributes to fevers and the bodily wasting in tuberculosis,' he continued, and the way in which an infected person responds to TB may determine whether the illness is slight or severe and chronic.

However, Dr McGuire said that the gene is widespread in the Gambian population which suggests that it may confer other, as yet unknown advantages, in combating other diseases.