Final Activity Report Summary - GEN_MAP_MALARIA (Genomic fine-mapping of malaria susceptibility loci) Malaria is a major cause of disease and death in tropical countries. Every year, more than 300 million cases of malaria are reported and more than 1 million died, manly children in sub-Saharan Africa. The genetic basis of resistance/susceptibility to malaria is very complex. Although some progress has been made towards the discovery of genetic factors responsible for malaria, the functional role of those factors is unknown in most case. My main objective was to apply state-of-the-art technologies to discover functional polymorphisms on the human genome that may harbour malaria susceptibility/resistance genes. I used the allele specific Transcript Quantification (ASTQ) approach to find function genetic variation that causes differential expression between alleles of genes. Genetic variants responsible for different allelic expression might have an important function in disease susceptibility/resistance.I applied the ASTQ approach on 6 genes around the TNF gene since TNF and other surrounding genes have been proposed to be associated with severe malaria. However, it has not yet been conclusively shown what the causative functional polymorphisms are. I also applied the ASTQ approach on the TLR9 gene because it has been recently reported that TLR9 is activated by the malaria pigment hemozoin. It is possible that this gene is important in mediating the first response against the parasite by activation of innate immune system. The ASTQ approach was used to compare the expression of the alleles of the selected genes between several unrelated individuals with ancestry from northern and western Europe and also between individual from Ibadan, Nigeria. In this project the ASTQ approach enabled us to detect at least in 3 genes differences of great magnitude in expression of the alleles between individuals. The TLR9 had the highest allelic differences between individuals. This type of analysis is extremely useful to provide candidate genes for further disease association analysis. In this project, the ASTQ data highlighted TLR9 as a possible candidate gene for malaria; therefore this gene was used in a small malaria case control study. We analysed Kenya, Gambian and Malawi samples that include controls and individuals with cerebral malaria, severe anaemia and other severe malaria cases. No significant results were obtained, however a small suggestion of association of TLR9 with cerebral malaria in children from Malawi was observed. More samples are needed to strengthen the association and confirm this observation.Overall, the results suggest that as denser genetic variants maps become available and high-throughput genotyping technologies are developed, it will be easier to identify functional regulatory polymorphisms that would be a practical means to identify genes for complex traits and diseases.This work involved the technical development and validation of mass-spectrometry based ASTQ. It had also required a lot of work to develop a large archive of cell lines. This project had also provided me training in human genetic epidemiology, genomic informatics and statistical genetics
