THURSDAY, Nov. 7, 2002 (HealthDayNews) -- Scientists have pinpointed a gene mutation that helps protect people from the worst ravages of malaria.
The finding has important implications for both preventing and treating the disease, which strikes half a billion people and kills 3 million worldwide every year.
"We're excited by it," says Dr. Brice Weinberg, a co-investigator of the trial and a professor of medicine at VA and Duke University Medical Centers. "This is not the only factor that operates in people to help protect them against severe disease. There are other genetic variations like sickle cell trait but, in looking at the degree of protection of known genetic variations, this appears to be as powerful as any of them identified. So it is important."
The results appear in this week's issue of The Lancet.
People with sickle cell trait (those who carry a gene for sickle cell anemia but who do not actually have the disease) are less susceptible to malaria.
Other experts in the field are also excited by the news.
"It looks like it's a really large effect, so that makes it particularly important because then it's reasonably likely to point to a mechanism that can protect people from the most severe consequences of malaria infection," says Kenneth Vernick, an associate professor of medical and molecular parasitology at New York University School of Medicine. "It could be possible to design a way to reproduce that effect in people who don't have the gene."
Earlier researchers had already shown that nitric oxide could inhibit the growth of parasites in test tubes. The next logical step -- and the one undertaken by the international team involved in this study -- was to search for variants of the gene, called NOS2, that regulates the production of this gas.
The efforts paid off: After examining the DNA of 1,291 Tanzanian and Kenyan children, some of whom were healthy and some of whom had malaria, the investigators found that the children with a specific mutation (or polymorphism) in the NOS2 gene were much less likely to get severely ill. In fact, Tanzanian children with the gene variant had an 88 percent lower risk of becoming ill than those without the variant. Kenyan children with the mutation had a 75 percent lower rate of developing severe malarial anemia.
Children with the mutation did indeed produce more nitric oxide, which could be protecting against severe disease in one of a number of ways. It could be preventing the infected red blood cells from sticking to the lining of the blood vessels and clogging blood flow to various tissues, such as the brain. It could be reducing the malaria parasites' ability to multiply in liver and blood cells or it could be reducing the production of certain inflammatory chemicals (cytokines) that can exacerbate the disease.
Although excessive nitric oxide can result in inflammation, this effect was not seen here. It's possible those with the gene polymorphism are able to produce higher levels of nitric oxide in response to infection.
The gene mutation is a good example of evolutionary selection at work. "The gene is favored because it produces more nitric oxide, which protects against malaria, so there's a greater chance of not dying, having children and passing the variant gene on to the next generation," Weinberg explains.
Interestingly, nitric oxide also plays a role in malaria infection in mosquitoes, which are the vector of the disease, Vernick says.
"A variation in nitric oxide is associated with decreasing the ability of the mosquitoes to transmit the infection," he says. "To find a similar mechanism in humans suggests that there's something here that malaria parasites really don't like in any developmental stage of the life cycle."
Other important aspects of the research are that the gene variant was found in two different countries and that it was protective against two separate forms of malaria. New research will be looking at whether the gene is present in individuals in Indonesia. That research will be done in collaboration with Indonesia's National Institute for Health Research and Development.
Prevention and treatment strategies would seek to reproduce the mechanism of the mutated gene. This could happen any number of ways. One would be to develop a drug that would increase nitric oxide levels in the right place (for instance, blood cells, liver cells and blood vessels) at the right time. Another would be to stimulate the body somehow to produce the needed nitric oxide. Drugs that provide nitric oxide are already used in cardiology but would not be appropriate to treat malaria.
Nitric oxide may also play a role in prevention, with nitric oxide production in response to malaria vaccines playing an important role in the development of immunity to malaria, say both Weinberg and a co-investigator, Dr. Nicholas Anstey, an associate professor of medicine at Menzies School of Health Research and Flinders University Northern Territory Clinical School in Darwin, Australia.
The new research comes close on the heels of the announcement last month that researchers had mapped the genetic blueprints of both the main malaria parasite and the mosquito that most frequently transmits it to humans.
"This complements that because we think it's an important finding in understanding the other part of the triangle, how humans respond to the malaria parasite," Anstey says. "It's an important part of the jigsaw of understanding of why some people get severe malaria and why other people get a bit of a fever and why some people die. It's an important part of that jigsaw."
It may also be applicable to other infectious diseases such as tuberculosis, Weinberg says.
What To Do
For more on the global threat of malaria, visit the World Health
Organization or the Malaria
Vaccine Initiative. Learn about how to avoid malaria while traveling to endemic areas from the U.S. Centers for Disease
Control and Prevention.
