Genetic Variant Protects People Against Malaria

An international team of scientists has discovered a novel genetic trait that protects its carriers against the deadliest forms of malaria, while people without the trait are more likely to succumb to its fatal consequences.

This trait — a mutation or “polymorphism” in the NOS2 gene — controls the production of nitric oxide, a small chemical that can kill parasites and prevent malaria disease. Results of their study are published in the Nov. 9, 2002, issue of The Lancet.

The genetic variant explains why some people with malaria have only mild symptoms and recover fully, while others develop severe disease that may progress to death, said researchers from the University of Utah, the Durham Veterans Affairs (VA) Medical Center, Duke University Medical Center, the U.S. Centers for Disease Control and Prevention, Tanzania and Kenya.

“Malaria is a worldwide epidemic, affecting twice the population of the United States every year,” said Brice Weinberg, M.D., professor of medicine at the Durham VA and Duke University Medical Centers and principal investigator on the study. “Drug resistance to malaria is rampant, so our ability to artificially duplicate the benefits of this genetic trait would be enormous.”

People with the NOS2 gene variant make higher levels of nitric oxide, and the nitric oxide protects them from the extensive tissue and brain damage normally caused by the malaria parasite, said Dr. Maurine Hobbs, lead author and research assistant professor of internal medicine and human genetics at the University of Utah.

The team’s ultimate goal is to develop a simple treatment that boosts levels of nitric oxide to treat and prevent malaria, a prospect that the researchers say is well within their grasp.

Nitric oxide works by reducing the malaria parasites’ ability to multiply in liver and blood cells, preventing infected red blood cells from adhering to the lining of blood vessels, and decreasing the production of inflammatory chemicals (cytokines) that exacerbate the disease. Thus, it reduces the most deadly effects of malaria, which target the blood and vital organs such as the brain, said Dr. Nick Anstey, associate professor of medicine at the Menzies School for Health Research in Darwin, Australia.

While excessive nitric oxide can be harmful and causes inflammation in diseases such as arthritis, Anstey said that nitric oxide can also be beneficial by protecting against infections and preventing damage to cells and organs.

“Nitric oxide can be extremely useful when it is produced by the right cells, at the right levels, and at the right time,” said Anstey. Interestingly, he noted, the NOS2 gene variant does not prevent malarial infection; it simply renders the malaria parasite less harmful to bodily systems.

In fact, the NOS2 gene variant confers such overwhelming protection that Tanzanian carriers have an 88 percent lower risk of becoming ill with malaria than those without the trait, the study showed. In Kenya, its carriers have a 75 percent lower rate of developing severe malarial anemia. The two groups of patients consisted of 1,291 children who lived in highly mosquito- and malaria-infested areas of the two countries. The researchers analyzed blood and urine samples to demonstrate that people with the NOS2 polymorphism had higher levels of nitric oxide.

Weinberg said they believe that evolution has favored this protective mechanism for individuals who are most often exposed to malaria. Not surprisingly, then, Caucasians do not possess this genetic mutation, so they are at much higher risk for severe malaria. While malaria is seemingly a remote possibility in the heartland of America, the disease was once prevalent in the parts of the U.S. It was virtually eliminated by the 1940s through better mosquito control and improved living conditions, yet the disease periodically emerges in the U.S., even today.

Only about 1,200 malaria cases are reported in the U.S. yearly, and it is unlikely to ever reach epidemic proportions here, but malaria is rampant in much of Africa and Asia, infecting about 500 million people each year. Despite some advances in treatment, malaria continues to be deadly — a malaria death occurs every 30 seconds worldwide.

Many of those infected with the malaria parasite may have no symptoms or only mild flu-like symptoms. However, others progress to more severe disease with extreme fatigue, fever, and chills. A third of these victims with severe disease — mostly children and pregnant women — succumb to more deadly consequences, either cerebral malaria or severe anemia.

In cerebral malaria, red blood cells containing the malaria parasite stick to the lining of blood vessels, causing blockages and decreasing blood supply to parts of the brain. Up to one-third of children with cerebral malaria die despite treatment. In severe anemia, parasites gobble up hemoglobin, destroy red blood cells and block blood formation until the patient is beyond rescue. Even with the best of current treatments, more than 1 million people die each year of severe malaria. The newly identified NOS2 gene polymorphism — called C-1173T NOS2 — protects against both kinds of malaria.

In addition to investigators from Duke, Utah, Australia and the CDC, researchers from the Hubert Kairuki Memorial University in Tanzania, and the World Health Organization in Switzerland contributed to the work. The research was supported by the National Institutes of Health, the U.S. Veterans Affairs, the U.S. Agency for International Development and the U.S. Centers for Disease Control and Prevention.