22 December 2009
This news post is no longer up to date. For a look at our more recent work on this area, please read our report Pathogen genomics into practice.
The most common known enzyme defect in humans is glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked recessive disorder. G6PD plays an essential role in protecting cells from oxidative damage, this is particularly important for red blood cells which are at substantial risk due to their role as oxygen carriers. Mutation in this enzyme can lead to anaemia, which is usually as a result of exposure to infections, certain foods or medication. In newborns, symptoms may include neonatal jaundice, caused as a result of the breakdown of red blood cells. G6PD deficiency is particularly prevalent in parts of Africa, the Middle East, and South Asia, which are also regions of the world where malaria is endemic and consanguinity is high. Although it has been suggested that G6PD mutations offer protection against malaria, much like mutations that cause sickle cell disease, a clear link had not been made between these mutations and infection with malaria parasites.
In an article published in Science, Louicharoen et al. investigated if one particular variant of the G6PD gene known as Mahidol, had an effect on survival following infection with two different species of the malaria parasite - plasmodium vivax and plasmodium falciparum [Louicharoen et al. (2009) Science 326:1546-1549]. Through genotyping the region encompassing the G6PD gene of individuals from a particular ethnic group in Thailand – the Karen, the researchers were able to identify alleles that had recently undergone positive selection. The Mahidol allele was shown to have undergone recent strong positive selection in this population, suggesting that possession of this allele was advantageous. They then went on to investigate how possession of this variant influences parasite numbers, by following clinical episodes of malaria in individuals whose G6PD-Mahidol genotype was known. The density and species of parasite they were infected with was monitored over a seven year period. Although possession of the Mahidol variant had no effect on the number of clinical cases of malaria caused by either parasite, it did have an effect on parasite density. The mean P.vivax density was reduced by 30% in females who were heterozygous for the variant and 61% in those who were homozygous in comparison to females who did not posses this particular variant. In males who can only possess one copy of this mutation as it lies on the X-chromosome, parasite density was reduced by 40%. Possession of this genotype did not influence the density of P.falciparum.
The mechanism by which this protection is conferred is not known. The authors postulate that it may be due to the increased sensitivity of P.vivax to oxidative stress. As G6PD deficiency leads to increased oxidative stress in red blood cells, this may in turn have a negative influence on the parasite. As such, individuals who possess this mutation have some protection against malaria.