Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya:

Malaria causes high levels of mortality in many tropical areas, most commonly due to severe acute anaemia, cerebral malaria and respiratory distress. Repeated exposure to uncomplicated malaria episodes is also responsible for high levels of childhood anaemia and under-nutrition. Over time this has significantly affected the human genome, with variations having arisen that help to protect against these adverse health consequences.

The most commonly known genome variants are the classic red blood cell variants sickle cell trait (HbAS) and the a+thalassaemias. KWTRP scientists set out to study a range of other candidates and have established the existence of more than 13 that offer variable degrees of protection against malaria.

Their study aimed to verify the importance of specific candidates that could provide insights into the pathophysiology of severe malaria and that might be used to underpin the development of new approaches to its prevention and treatment.

The case control study had its participants drawn from 2244 children under the age of 14 years who were admitted to the Kilifi County Hospital and transferred to its High Dependency Unit with symptoms of severe malaria and 3949 infants as controls. The cases were then further categorized into the common clinical sub-types of severe malaria and were also classified based on their hospital in-patient survival status.

Using a case-control approach which is the most efficient approach to exploring associations, the team studied 121 variants of 70 genes. The 121 variants had been suggested by other studies as to be important with most of the previous studies having not been large enough to prove associations conclusively, or because there were biological reasons to believe that they could be important.

The data for many of these genes have previously been inconclusive. The most important and interesting finding related to Dantu, which has only been studied once before and not in such detail. This study shows how strongly protective this new gene is – almost 80% protection in its homozygous form and about 40% in its heterozygous form. In addition, the study also shows that this protection is equally strong against all the common forms of malaria. The most likely way in which Dantu might protect is by stopping parasites from invading the red cell – Dantu is a variant form of glycophorin that is an important mediator of parasite invasion into the red cell.

 

Parasite densities – the concentration of parasites in the peripheral blood stream – among children presenting with malaria are important because they might indicate mechanisms by which individual genes lead to protection. For example, a second red cell genetic variant ATP2B4, which controls calcium movements across the red cell membrane, is associated with lower densities suggesting that it might slow down the multiplication of parasites in red cells. Haematological indices are also interesting because many protective red cell genes are associated with small red cells – a fact that might be important to their mechanism.

 

These genetic variants are very good news for the people who have them. Work still remains in learning how they work and being able to translate this to the development of drugs and vaccines based on the same principals. Any vaccine that offered 80% protection against any disease would be considered very attractive.