Study sheds new light on the protective effects of genetic variants against malaria - notably those related to red blood cell structure or function.

The results of the study, published recently in The Lancet Haematology, found substantial links between the risk of severe malaria and polymorphisms (genetic variations) in 15 genes. Notably, the majority of the most significant malaria-protective genes were related to the structure or function of red blood cells, which are the main target of the disease in humans.

The researchers behind the study are now looking to identify the specific mechanisms by which these polymorphisms protect against malaria, which could be used to develop new treatments.

Genetic investigation

Based in Kilifi County in Kenya, the study team recruited over 2,000 children presenting with symptoms of severe malaria, and an additional 4,000 children as a control group. With genetic factors playing a key role in determining an individual’s risk of developing malaria, the aim of the study was to investigate whether specific genetic variations might provide natural protection against the disease, and could therefore be used to underpin new approaches to treatment.

Using blood samples collected from the cohorts, researchers investigated 121 variants in 70 genes that they suspected were involved with the susceptibility of severe malaria. Following analysis, polymorphisms in 15 of the 70 genes investigated were found to have associations with risk of severe malaria. Although data for some of these genes have been reported previously, the team’s findings reveal that the most significant links were between genes with a role in red blood cell structure and function.

Blood barriers

Notably, the findings indicate that a recently-discovered genetic variant – the rare Dantu blood group – is associated with particularly high levels of protection against severe and complicated malaria. The team found that Dantu was equally protective against all of the most common subtypes of severe malaria, including cerebral malaria, respiratory distress and severe malaria anaemia.

In addition, the researchers found that variation in ATP2B4 – a gene that controls the movement of calcium into red blood cells – was associated with high levels of malaria resistance.

The findings also provide further confirmation of the significant protective advantage of several well-established candidate polymorphisms, including inherited red-blood-cell characteristics resulting in sickle-cell trait, G6PD deficiency, and blood group O. 

Identifying anti-malaria mechanisms

In order to understand how these polymorphisms might be used in the development of new malaria treatments, the researchers now need to investigate the precise mechanisms through which these genetic variations protect against the disease.

“Because this study is only observational, further work will be needed to confirm the causal association between these genes and malaria resistance and to elaborate the mechanisms involved,” explains the paper’s joint last author, Professor Thomas Williams.

“We are conducting further studies using different designs to investigate the effect of these genes in other population groups and to study their protective mechanisms in the laboratory.”

‘Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study’ by Carolyne M Ndila et al., is published in The Lancet Haematology.

Image credit: 'Mosquito (Anopheles stephensi)' by Lauren Holden. Lauren Holden. CC BY.