GEN_MAP_MALARIA · Genomic fine-mapping of malaria susceptibility loci
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2003-12-01 → 2005-11-30
- EU contribution
- €168,799
- Participants
- 1
- Scheme
- EIF
Lines connect the coordinator with its partners. CORDIS does not always give exact coordinates for projects before 2014. These points are placed at city or country level.
Results in brief
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
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OXFORDCoordinatorCity levelUnited Kingdom
Links
Data: CORDIS, © European Union