'Host genetic susceptibility to tuberculosis and malaria in Africa'

Humans have been afflicted with tuberculosis (TB) and malaria since antiquity. Although largely eradicated from the developed nations of Europe and North America, these diseases have remained a constant threat in the developing world, especially Asia and Africa. TB a~d malaria are multifactorial infectious diseases which have been shown to have a strong genetic component, through twin studies, genome-wide linkage studies and candidate gene association studies. A partial genome screen, utilising microsatellite markers from chromosomes 2, 5, 6, 15, 19,20,21 and 22, ofTB in Algerian affected sibling pair families was undertaken for this thesis. The marker D5S641 on chromosome 5 located 'a region (5qI4.2) suggestive of linkage in TB (LOD 1.48, P=0.005). This thesis also reports research on candidate genes for TB and malaria' in West Africa. The incidence of TB in West African males is more than twice that of females. Nevertheless, no association was found between TB and the Y chromosome polymorphisms studied. Analysis of Y chromosome SNP markers confirmed that case and control groups were adequately matched in the West African' TB study. The Y chromosome data ·also showed that the paternal gene pool of these West African populations were distinct from those of their geographical and linguistic neighbours. Conversely, the evidence from mitochondrial DNA supported a proposed migration of females into the study region, resulting in a greater similarity of the maternal gene pools among populations in West Africa. ' This thesis focussed particularly on candidate genes involved in pathogen pattern recognition receptor pathways, and identified several such genes that appeared to be associated with TB. Heterozygotes for the TIRAP SNP, rs8177374, were found to be protected against TB (OR=4.38, 95% C.1. 1.37 to 13.96, Pcorrected=O.013), supporting parallel work implicating this variant in protection against other infectious diseases. A non-synonymous coding SNP, rs1990760, of IFIHI, a gene which encodes a cytoplasmic receptor for certain pathogen-associated molecular patterns, also provided evidence of association with TB, with heterozygotes for the SNP being more susceptible (OR=1.83, 95% C.I. 1.27 to 2.62, PcorrecterO.OOl). TT homozygotes for the non-synonymous coding SNP, rs1884444, of IL23R also showed greater susceptibility to TB than individuals with the alternate allele, G (OR=1.50, 95% C.1. 1.05 to 2.14, PcorrecterO.026). There was no evidence for association of TLR9, TICAM2, IRF3, IRF5, IRF7 and MCPI with TB, nor PKLR and BTLA with malaria. ' . These findings ·add to our understanding of the multigenie basis of variable resistance to these· diseases and provide further evidence for the importance of innate immunity genes in affecting susceptibility.EThOS - Electronic Theses Online ServiceGBUnited Kingdo