Each year, about a million people are killed by malaria. But even in countries where the disease takes a heavy toll, new research finds, the risk can vary: A subtle difference in a single gene can cut the risk of developing a life-threatening case of malaria by up to nearly 90% in people who have already been infected.
The gene mutation causes people to ratchet up production of nitric oxide (NO), a gas that plays a role in a variety of physiological processes. Previous studies with rodents found that NO can guard against malaria and other diseases, but no one was sure if it had the same protective effect in humans.
Looking for an answer, a team led by hematologist Brice Weinberg of the Veterans Affairs and Duke University Medical Centers in Durham, North Carolina, sampled DNA from 185 Tanzanian children. All had been exposed to malaria, and 47 had remained healthy. The researchers looked for mutations in and around the gene that encodes inducible nitric oxide synthase (NOS2), the enzyme that makes NO. One subtle mutation in the NOS2 gene's promoter region--its DNA on-switch--turned up more often in the healthy children than in the sick. Children with the mutation had higher than normal NO levels in their blood and urine, suggesting that the gas could be protecting them.
The team then analyzed DNA samples and clinical data from a 5-year Centers for Disease Control and Prevention study of 1106 children in Kenya. They again found that the mutation in the NOS2 promoter had a protective effect. "Overall, the mutation lowered the risk of severe malaria by 88% in Tanzania, and 75% in Kenya," says molecular geneticist Maurine Hobbs of the University of Utah in Salt Lake City, a co-author of the study, which appears in the 9 November issue of The Lancet. Exactly how NO protects isn't yet clear.
"The story told by this study is very appealing and logical," says clinical immunologist Brian Greenwood of the London School of Hygiene & Tropical Medicine in the United Kingdom. This isn't the first mutation thought to protect against malaria (sickle cell anemia does too, for instance), he says, but "this study is one of the most compelling because they have demonstrated a connection between genetics, NO production, and clinical status."