Malaria due to Plasmodium falciparum kills over a million African children each year. We need to get a better understanding of natural mechanisms of host defence against the parasite, to help in the search for better ways of treating severe malaria and for an effective malaria vaccine. This proposal aims to understand the association between severe malaria and polymorphisms of TNF, the gene encoding tumour necrosis factor. Several different associations have been observed between TNF and severe malaria, but it has not yet been conclusively shown that that the causative polymorphisms are in TNF itself, as opposed to neighbouring genes that are in linkage disequilibrium. The genomic region where TNF is located contains a rich variety of immune genes as well as several poorly understood genes that are suspected to have animmunological function. My goal is to carry out genomic fine-mapping of the region of the human genome around TNF, to determine the causal basis of associations between TNF polymorphisms and susceptibility to severe malaria in African children. I will address two fundamental questions:
(1) Considering a total of 24 genes distributed over a 320kBinterval (from MICA to CLICI) what is the full range of genes that are associated with severe malaria?
(2) Can we narrow down the functional polymorphism(s) responsible for the disease association by a combination of detailed haplotypic analysis and large-scale epidemiological studies in different populations? To address this problem I will begin by defining the haplotypic structure of the 320kb region around TNF in a West African population, and then use the most informative polymorphisms to fine-mapping disease association in large case-control and family-based studied of African children with severe malaria. This project will provide training in human genetic epidemiology, state-of-the-art genotyping technology, genomic informatics and statistical genetics.
Fields of science
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