The molecular genetic approach to malarial pathogenesis and immunity.

It is poorly understood why some malarial infections are fatal while others resolve without complications. Host genetic factors are partly responsible. More than ten specific susceptibility determinants have already been defined, including both structural and regulatory polymorphisms of erythyrocytes and of the immune system, and it is likely that many more have yet to be discovered. A vast number of DNA polymorphisms, scattered throughout the human genome, cause individual variation in probably all immunological and biochemical processes. Advances in DNA technology offer the prospect of screening thousands of candidate genes for association with susceptibility to severe malaria in large multicentre case-control and family-based studies. Saturation mapping of candidate gene regions, combined with cellular and molecular analysis of disease-associated polymorphisms, is essential for understanding the functional basis of the genetic associations that such an exercise will generate. This information will pinpoint critical molecular pathways in immunity and pathogenesis and may lead to fundamentally new strategies for treatment and prevention of severe malaria.