The health consequences of genetic variants that have been selected by malaria, with a particular focus on polymorphisms affecting the red blood cell

Efforts to eliminate malaria are threatened by the spread of resistance to the drugs and insecticides needed to control the disease. Through a massive, multi-country genome-wide association study conducted in the last few years, we now have unequivocal evidence for high-level protection against severe falciparum malaria by a number of new human genetic polymorphisms. Most relate to the red blood cell (RBC), the primary target of the malaria lifecycle in humans. The challenge now is to turn this knowledge into new drugs and vaccines. Through this fellowship, I will use the unique opportunities available to me in Kilifi, Kenya, to discover the protective mechanisms afforded by four key polymorphisms - mutations in GYP, ATP2B4 and the ABO and Knops blood group antigens - and to document their wider consequences. I will take a comprehensive and multi-disciplinary collaborative approach that will include studying the effect of these genes on: (i) malaria- and non-malaria-specific disease epidemiology; (ii) RBC structure and function; (iii) P. falciparum invasion both in vitro and in vivo through experimental human challenge; and (iv) in vitro correlates of malaria severity. These studies will be essential in determining the translational potential of these associations and informing future work.