The long-term goal of this research is to extend our understanding of the biological basis of evolutionary relationships between Duffy (Fy) blood group polymorphism and malaria. The specific hypothesis to be tested is that the molecular polymorphism responsible for Duffy-negativity (Fy[a-b-1) has emerged in Papua New Guinea (PNG) because it confers resistance to Plasmodium vivax blood-stage malaria. Our studies have discovered the Y GATA- I promoter mutation, which eliminates erythroid Fyb expression in Africans, on the FY* A allele in Melanesians residing in a P. vivax endemic region of PNG. This allele, therefore, appears to be independent of African origin. Flow cytometric analysis correlates this mutation with reduced erythroid Fy expression (FY*Anull). This finding in PNG provokes unresolved questions regarding the evolutionary relationship between Fy(a-b-) and malaria, such as how a """"""""non-lethal"""""""" malaria injection may contribute to selection of a mutation that has reached fixation in many African populations, and how susceptibility to P. vivax influences infection and morbidity from other malaria species, including P. falciparum. Unlike African Fy(a-b-), discovered in the absence of the parasite, FY*Anull emerges in a setting which permits future evolutionary study.
The specific aims are to: 1. Assess the distribution patterns of FY*Anull in communities within and surrounding the Wosera and their relationship to the intensity of malaria transmission and epidemiology of P. vivax, P. falciparum, P. malariae, and P. ovale infection. 2. Examine population genetic evidence implicating selection of the FY*A/FY*Anull genotype through family-based studies. 3. Examine susceptibility to P. vivax infection and morbidity comparing individuals with FY*A/ FY*Anull and FY*A/FY*A genotypes.
This aim will include prospective matched cohort studies to determine whether the FY*A/FY*Anull genotype is associated with reduced susceptibility to P. vivax infection, morbidity or changes in infection with other malaria species relative to FY*A/FY*A.
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