PROJECT SUMMARY SickleGenAfrica is a genomics network that aims to test the overarching hypothesis that genetic variation in cyto-protective defenses against hemolysis influences the risk of organ damage in sickle cell disease (SCD). The focus of project 2 is to determine Genome-wide determinants of the risks of malaria complications in SCD. Background of the project: Malaria in SCD is associated with severe complications and an increased risk in mortality. Hemolysis is a key process that contributes to the pathogenetic processes in both malaria and SCD particularly with respect to acute and chronic end-organ damage leading to severe anemia, lung and brain injury. 4 countries in SickleGenAfrica (Ghana, Tanzania, Nigeria and Cameroon) and US collaborators (Pittsburgh and Morehouse) have experience and expertise in both conditions and intend to use established resources to interrogate the two conditions as well as establish a murine model to evaluate malaria in SCD. Specific aims: (1) To characterize the phenotype of severe malaria in SCD patients, and determine the relationship between variations in HCP genes and malaria disease phenotype/severity. (2) To investigate the inflammatory response (cytokines/chemokines and adhesion molecules) in SCD patients with malaria, and examine the relationship with HCP levels and risk of severe malaria. (3) Functionally validate association between HCPs and severity of malaria in transgenic SCD mice. The significance of the proposed research and relevance to public health: SCD and malaria are both disorder of public health significance (annual SCD births of 300,000 globally; 3.3 billion people living in 106 countries are at risk of malaria infection) with high mortality (Up to 90% childhood mortality in SCD; 438 000 malaria deaths). Accurate description of disease expression and the identification of genetic and environmental modifiers of disease will improve the diagnosis, management and prevention of malaria-related morbidity and mortality in SCD. The unique features and innovation of the project: (1) The first study with the largest SCD population (n=7,000) investigated for malaria. (2) Assessment of phenotypic description of malaria in SCD during acute and steady-state. (3) Evaluation of inflammatory response in malaria in SCD (4) Use of murine model to investigate malaria in SCD. The methodology to be used: We will enrol 7,000 SCD patients in 4 countries at clinic and evaluate patients during hospitalization. We will infect transgenic SCD and control mice with Plasmodium and measure levels of hemolysis cytoprotective proteins and inflammatory markers and evaluate disease expression focusing on hemolysis and anemia as well as end-organ damage to lung and brain. Expected results and description of how your results will affect other research areas: Description of phenotypic expression of co-morbidity of malaria and SCD, with identification of genetic and environmental modifiers of disease, emphasizing the role of hemolysis in both conditions.