Gene Region That Protects Children from Severe Malaria Identified

Researchers have identified a protective allele that was found to reduce the risk of severe malaria by almost 40% in children. [iStock/© MShep2]

The protective effect of the sickle cell allele and its increased prevalence in sub-Saharan Africa is evidence of the selection pressure that malaria has had on human evolution. However, remarkably few other polymorphisms have been observed to be associated with parasite resistance in large population studies.      

Now, researchers with MalariaGEN—an international network of scientists and clinicians spread across Africa, Asia and other malaria-endemic regions of the world, largely funded by the Wellcome Trust—conducted a genome-wide association study (GWAS) to try and explain why in endemic regions some children develop severe malaria and others do not.

Comparing the DNA from 5,633 children with severe malaria with the DNA of 5,919 children without severe malaria, investigators identified a locus that may explain the disparity in the development of severe malaria. To be certain of their initial results, the scientists replicated the study in a further 14,000 children. 

The new locus identified was near a cluster of genes that code for proteins called glycophorins that are involved in the malaria parasite's invasion of red blood cells. Though many different malaria resistance loci have been postulated over the years, this is one of very few that have stood up to stringent testing in a large multicenter study; the others include the genes for sickle cell and the O blood group.

“We can now say, unequivocally, that genetic variations in this region of the human genome provide strong protection against severe malaria in real-world settings, making a difference to whether a child lives or dies,” explained co-senior author on the study Dominic Kwiatkowski, M.D., professor at the Wellcome Trust Sanger Institute and the Wellcome Trust Centre for Human Genetics. “These findings indicate that balancing selection and resistance to malaria are deeply intertwined themes in our ancient evolutionary history.

The findings from this study were published recently in Nature through an article entitled “A novel locus of resistance to severe malaria in a region of ancient balancing selection.”

“This new resistance locus is particularly interesting because it lies so close to genes that are gatekeepers for the malaria parasite's invasion machinery,” stated Dr. Kwiatkowski. “We now need to drill down at this locus to characterize these complex patterns of genetic variation more precisely and to understand the molecular mechanisms by which they act.”

The researchers found that the protective allele was found most commonly among children in Kenya in East Africa and reduced the risk of severe malaria by about 40% in Kenyan children, with a slightly smaller effect across all the other populations studied.

“These findings provide new insights into the human and Plasmodium genetic interaction that are determined by their co-evolution,” noted co-author Ogobara Doumbo, Ph.D., professor at the Malaria Research and Training Center at the University of Bamako in Mali. “How these findings could be used in public health settings, as a marker of individual and population risk of malaria infection, is the next step. Applying the findings in this way will only be possible by training a critical mass of African scientists in genomics and big data management and analysis.”

Researchers have known for decades that the glycophorin cluster of genes is highly variable, but until recent advances in next-generation sequences it was not possible to show that this genetic variation was responsible for protecting people against severe malaria.

Interestingly, the new genetic resistance locus lies within a region of the genome where humans and chimpanzees have been known to share particular combinations of DNA variants, known as haplotypes. This would indicate that some of the variation seen in contemporary humans has been present for millions of years.

“This work is an excellent example of how genuine large-scale collaboration can tap into the power of modern genomic science,” stated co-author Kevin Marsh, M.D., professor at the Kemri-Wellcome Research Programme in Kilifi, Kenya. “The risk of developing severe malaria turns out to be strongly linked to the process by which the malaria parasite gains entry to the human red blood cell. This study strengthens the argument for focusing on the malaria side of the parasite-human interaction in our search for new vaccine candidates.”