LONDON — The list of single gene defects that provide protection against infectious diseases for those who carry a single copy of the faulty gene is growing longer.
Probably the best known example of this phenomenon is the protection against malaria afforded to people who carry one copy of the gene which — in a double dose — causes sickle cell anemia. There also has been speculation that a single copy of the cystic fibrosis gene helps to protect carriers against cholera.
Now, however, scientists in Oxford, U.K., and in Papua New Guinea have proved that the thalassemia gene protects children against malaria — and against other infections, too.
David Weatherall's team at the Institute of Molecular Medicine, in Oxford, and colleagues at the Papua New Guinea Institute of Medical Research report their findings in a paper in the Dec. 23, 1997, issue of the Proceedings of the National Academy of Sciences (PNAS), titled "a+- Thalassemia protects children against disease caused by other infections as well as malaria".
There are several different types of thalassemia, each leading to reduced or absent synthesis of the a- or B-globin chains that make up adult hemoglobin. This molecule normally has two a and two b chains (a2b2). There are two a-globin genes on each chromosome 16 (aa/aa) and, in a+-thalassemia, one gene of the pair is deleted.
Thus it is possible for an individual to be homozygous (-a/-a) or heterozygous (-a/aa). Heterozygotes suffer no clinical symptoms at all, while homozygotes experience mild anemia, with hemoglobin levels 1-2 g/dl lower than normal values.
Weatherall and his colleagues had previously discovered a geographical correlation between the distribution of malaria and that of a+-thalassemia in Papua New Guinea. He told BioWorld International, "In Papua New Guinea, where malaria is present all the time and every child has had it by the age of one year, there is a very high frequency of a+-thalassemia. But if you go up into the mountains of Papua New Guinea, where above a certain altitude malarial mosquitoes do not breed, there is no a+-thalassemia. When you start going south to the islands of Melanesia, malaria becomes less common and so does a+-thalassemia."
These observations were "suspicious," said Weatherall, "but we had to go one step further and answer the basic question: Does having a+-thalassemia protect you against the really bad effects of malaria?"
To do this, he and his colleagues carried out the study reported in PNAS. This was conducted in Madang province of Papua New Guinea, where about 55 percent of the local population is homozygous for a+-thalassemia and 37 percent is heterozygous.
The research group identified children who had been admitted to Madang hospital with very severe malaria, as defined by criteria set out by the World Health Organization. For each of these cases, a control child was identified who came from the same village and was of the same age and sex.
Weatherall said: "We then asked whether the children in hospital with severe malaria were more or less likely to have a+- thalassemia than those who did not. The answer was very clear-cut: there was a relative paucity of severe malaria in a+- thalassemic children. This genetic condition seemed to reduce their risk of being admitted to hospital with some very nasty types of malaria by about 50 percent."
The team also discovered something "totally unexpected," Weatherall added. For statistical reasons, it had included in its study children admitted to hospital with severe infections other than malaria. The researchers found that a+-thalassemia also made the children less likely to be admitted with other infections, such as respiratory infections, gastroenteritis and meningitis.
"We don't know the reasons for this," Weatherall said, "but the most likely reason is that malaria is a very debilitating disease, so that children who get it once or twice a year will probably be prone to other infections like respiratory infections.
"So it may be that all this is telling us is that malaria is pretty bad for you and that if you are protected from it in this population, this has a profound effect on your health in general."
Gene Pools Altered
Weatherall speculated that malaria has had such a devastating effect on human health that it has caused a whole series of changes in the gene pools of those populations worst affected by it — even though humans probably have been exposed to the disease for only a relatively short period lasting perhaps a few thousand years.
Recent studies have shown, he said, carriers of the sickle cell anemia gene enjoy about 80 percent protection against severe malaria — higher even than that offered by a+-thalassemia. There also is evidence genes of the HLA system have been modified by malaria.
The team's next goal is to find out how the mechanism of protection works. A related study by the same group has already provided some clues. The researchers took blood samples from 5,000 babies born on the island of Vanuatu and tested them to find out if they had a+-thalassemia. They then followed these children up to the age of four or five.
They found, during the first year of life, babies with a+-thalassemia were more prone to suffer from both the potentially fatal form of malaria caused by Plasmodium falciparum and the milder form caused by P. vivax. After the age of one, however, these children seemed to enjoy protection against malaria.
Weatherall concluded: "We speculate that perhaps early immunization plays a role, and that P. vivax may offer some cross-immunity to P. falciparum."