摘要：

Plasmodium falciparum and Mycobacterium tuberculosis infections collectively causeas many as five million deaths world-wide each year. In the most afflicted populations,currently available drugs and vaccines appear inadequate. By offering insight into thepathophysiology of diseases, genetic studies provide options for new therapeuticapproaches to major health problems. The results of case-control studies of geneticfactors associated with disease outcomes in malaria and tuberculosis in an Africansetting are presented in this thesis.Glucose-6-Phosphate dehydrogenase (G6PD) deficiency, the commonestenzymopathy of humans, affects over 400 million people. The geographical correlationof its distribution with the historical endemicity of malaria suggests that this disorderhas risen in frequency through natural selection by malaria. However, attempts toconfirm that G6PD deficiency is protective in case-control studies of malaria haveyielded conflicting results. Hence, for this X-linked disorder, it is unclear whether bothmale hemizygotes and female heterozygotes are protected or, as frequently suggested,only females. Furthermore, how much protection may be afforded is unknown. In twolarge case-control studies of over 2000 African children, I found that the commonAfrican form of G6PD deficiency (G6PD A-) is associated with a 46-58% reduction inrisk of severe malaria for both female heterozygotes and male hemizygotes. Amathematical model incorporating the measured selective advantage against malariasuggests that a counterbalancing selective disadvantage, associated with this enzymedeficiency, has retarded its rise in frequency in malaria-endemic regions.There is some evidence that two T helper cell subsets, Thl and Th2, regulatethe immune response and thus influence the course of infections in mammalian hosts.These T cell subsets are reciprocal and associated with distinct cytokine profiles. Th2T cell differentiation is promoted mainly by interleukin-4. Analysis of an IL-4 promoterpolymorphism indicates that homozygosity for a putatively upregulatory IL-4 promotervariant is associated with a signficantly increased risk for severe malaria whilstheterozygotes are protected against this condition.Epidemiological evidence implicates host genetic factors as major determinantsof variable susceptibility to tuberculosis. Most attempts to define the genetic factor(s)have focused on the HLA genes but only one result, an association of HLA-DR2 withincreased susceptibility to disease in Asian populations, has been reported with anyconsistency. The genetic component in tuberculosis is likely to be determined bymultiple genes and, therefore, in this study, the role of both HLA and non-HLAcandidate genes was investigated. No association was found with variants of themacrophage gene, NRAMP1, the homologue of which has been implicated in theregulation of genetic resistance in the mouse model. Examination of certain class I andclass II HLA alleles as well as the -590 interleukin-4 promoter polymorphism also didnot show any association with disease. However, heterozygotes for a promoterpolymorphism at position -238 of the tumour necrosis factor gene and homozygotesfor dysfunctional variants of the gene encoding the collectin, mannose binding protein,were both at increased risk of developing pulmonary tuberculosis.

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