Rare genetic disease protects carriers against malaria

Results show that human evolution has been shaped by malaria

Researchers from McGill University and the University of Toronto have discovered that the mutation which causes pyruvate kinase deficiency – a genetic disorder of blood cells – protects its carriers against malaria. This discovery demonstrates the profound influence of malaria on human evolution, a virtual “fingerprint” within the human genome itself, say the researchers. Their study was published April 16 in the New England Journal of Medicine.

The research was conducted by Dr. Philippe Gros of the Department of Biochemistry at McGill and Dr. Kevin Kain of the McLaughlin-Rotman Centre for Global Health at the University of Toronto, and colleagues at both institutions, and was funded by the Canadian Institutes for Health Research (CIHR). The study was first-authored by Kodjo Ayi, a McGill post-doctoral fellow working in Dr. Kain’s lab.

Malaria is an infectious disease spread by parasites of the genus Plasmodium. Most common in tropical and subtropical regions, it is a global scourge with 350 to 500 million new cases – and one to three million fatalities – reported annually.

For its part, pyruvate kinase deficiency is an inherited genetic deficiency which causes the abnormal breakdown of red blood cells and hemolytic anemia. It is an autosomal recessive trait, which means both parents must carry the defective gene and pass it along for their offspring to develop the disorder.

The study stemmed from the discovery in Dr. Gros’s lab of a mouse strain that was particularly resistant to malaria, was later shown to carry a mutation that leads to pyruvate kinase deficiency.

“In previous mouse studies we showed that the anemia caused by pyruvate kinase deficiency actually protects the animals from the malaria parasite which attacks mice,” Dr. Gros explained.

In this follow-up study, conducted in partnership with Dr. Kain’s team in Toronto, the researchers showed that humans carrying the pyruvate kinase deficiency gene are similarly protected against malaria.

“We’ve proved that the malaria parasite does not invade the red blood cells or replicate nearly as well in those mutant individuals as in normal people,” Dr. Gros explained. “And even those cells which do get infected are eliminated much more quickly.”

Perhaps even more critically, Dr. Gros said, the study showed that individual bearing only one copy of the pyruvate kinase deficiency mutation (healthy carriers) are also protected against malarial parasites.

“These people carry only one copy of the mutation, they’re asymptomatic, they don’t have anemia. However, having one copy of the mutated gene is sufficient to impart significant protection against the malarial parasite” said Dr. Gros. “Although this isn’t proven yet, it’s starting to look like these mutations may have been preserved in the population because of evolutionary pressure from the malaria parasite.”

Though no therapies are likely to derive from this discovery, Dr. Gros said, it provides a fascinating window on how deadly pathogens like malaria have influenced human evolution.