Genetic Resistance to Malaria

Differences in the PKLR Gene Might Affect Malaria Symptoms

by Dr. Barry Starr, Stanford University

April 25, 2008

Almost half a billion people each year get malaria and it kills more than a million of these people. But some people are naturally protected from the disease. Research from Canada suggests that sometimes this resistance can be explained by a DNA difference in these people’s pyruvate kinase or PKLR gene.

This isn’t a surprising result since researchers had shown before that mice with differences in their PKLR gene are more resistant. The difference here is that the researchers showed that having this DNA difference might affect people’s symptoms too.

Blood Diseases and Malaria

Red blood cells lack mitochondria
which is why PKLR is so important.

The parasite that causes malaria, Plasmodium falciparum, spends part of its time in red blood cells. So anything that affects red blood cells might make things easier or harder for this parasite.

Changes in the PKLR gene definitely affect how red blood cells work. PKLR is a key gene in how they get their energy.

Red blood cells are unique in that they have no nucleus or mitochondria. The lack of mitochondria means that red blood cells get their energy differently than most other cells. They use a process called glycolysis.

An important gene in glycolysis is PKLR. People with defective PKLR genes suffer from something called pyruvate kinase deficiency. They tend to have severe anemia because their red blood cells have trouble getting the energy they need.

At first blush this doesn’t seem too helpful for someone about to get malaria. To avoid severe malaria symptoms, that person needs to suffer from severe anemia. Luckily the situation isn’t as bad as this sounds. The researchers showed that carriers for pyruvate kinase deficiency may get the benefits of less severe malaria symptoms too.

Remember, people have two copies of most of their genes—one from mom and one from dad. To end up with pyruvate kinase deficiency, a person needs for both copies of the PKLR gene not to work properly. Someone with a single broken copy doesn’t have the disease but may suffer less from malaria.

This is reminiscent of sickle cell anemia. Sickle cell anemia is caused by a defective Hb gene.

Under certain conditions, the red blood cells of people with sickle cell anemia form crescent shapes. The symptoms of the disease come from the crescent shaped red blood cells clogging up small blood vessels.

People who have just one defective Hb gene have very few symptoms. But these folks are resistant to malaria.

In fact, sickle cell anemia is the classic case of a disease that sticks around because being a carrier has an advantage. The protection from malaria is thought to outweigh the risk of having a child with sickle cell anemia.

More Information

Sickle Cell Anemia

Malaria and PKLR-Deficient Red Blood Cells

Things that affect red
blood cells can affect
the progression of
malaria too.

From the previous mouse work, the researchers thought that pyruvate kinase deficiency might be a lot like sickle cell anemia. In other words having just one defective PKLR gene might give a person some protection from malaria.

To show this, the researchers looked at how the malaria parasite could infect red blood cells from three groups of people. And what happened to these cells after they became infected.

The researchers looked at people with pyruvate kinase deficiency, carriers and people with “normal” PKLR genes. Of course they didn’t infect these any of these people. Instead, the researchers looked at what the parasites did to each of these people’s red blood cells in a dish in the lab.

The first thing the researchers looked at was how well the malaria parasite infected each of these people’s cells. The results were that the parasite had trouble infecting cells from people suffering from pyruvate kinase deficiency but did fine with carriers and people with two working copies of PKLR.

These results alone would suggest that only people with two broken copies of the PKLR gene are resistant to malaria. But the next set of results showed that carriers might be protected too.

The researchers looked at what happened to each group of red blood cells after infection. What they found was that infected carrier and diseased red blood cells were more likely to be gobbled up by cells from the immune system than were infected cells with no defective PKLR copies.

If the immune system gets rid of infected cells more quickly, then an infection might not be able to take hold as easily. So this result suggests that there might be some protection from malaria by being a carrier.

This work is still preliminary because it was all done in a lab. The next step will be to see if any of this is true with people who actually have malaria.

Researchers can also scan the DNA of people from various ethnic groups to see if being a carrier does carry an advantage. Sickle cell anemia is much more common in people whose ancestors came from areas where malaria was a problem. If the same is true for people with pyruvate kinase deficiency, then perhaps being a carrier for pyruvate kinase deficiency does give some protection from malaria.
Content provided by the Department of Genetics, Stanford University.