Human genetic susceptibility to tuberculosis : the investigation of candidate genes influencing interferon gamma levels and other candidate genes affecting immunological pathways

[摘要] The infectious disease tuberculosis (TB) is one of the leading causes of deathworldwide. The idea that infectious diseases are the most important driving force innatural selection and that they sustain frequent polymorphisms in the human genomewas formally suggested by Haldane in 1949. This hypothesis implicated the humangenetic component in the response to infectious disease. Today the involvement of hostgenetics in TB has been proven unequivocally and, together with environmental factors(e.g. nutrition and crowding) and the causative bacterium, Mycobacterium tuberculosis(M.tuberculosis), may influence the outcome of disease. As is evident, TB is a complexdisease and the implication for studying genetic susceptibility is that a number of geneswill be involved.Interferon gamma (IFN-7) is the major macrophage-activating cytokine during infectionwith M.tuberculosis and its role has been well established in animal models and inhumans. This cytokine is produced by activated T helper 1 (Th1) cells. These Th1responses can best deal with intracellular pathogens such as M.tuberculosis. Weselected twelve candidate genes based on the hypothesis that genes which regulate theproduction of IFN-7 may influence TB susceptibility. We also selected polymorphismsfrom 27 other candidate genes, which may affect immunological pathways involved inTB, to investigate as susceptibility factors based on the following hypotheses: 1)granulomatous diseases can share susceptibility genes; 2) gene expression studies doneby DNA-array analysis experiments may reveal TB susceptibility genes; 3) genomewidelinkage studies in TB can determine susceptibility loci and genes in this region arepossibly susceptibility factors; and 4) functional susceptibility polymorphisms in genesinvolved in immune-mediated diseases other than TB may contribute to susceptibility toTB.This research tested the association of 136 genetic polymorphisms in 39 potentiallyimportant genes with TB in the South African Coloured population. Well-designedcase-control association studies were used and we attempted to replicate these findingsin an independent sample set using family-based case-control designs (transmissiondisequilibrium tests (TDTs)). In addition, haplotypes and linkage disequilibrium (LD)in the candidate genes were also investigated.During the case-control analyses we found significant associations for 6 singlenucleotide polymorphisms (SNPs) in the following genes: SH2 domain protein 1A, tolllikereceptor 2, class II major histocompatibility complex transactivator, interleukin 1receptor antagonist, runt-related transcription factor 1 and tumour necrosis factorsuperfamily, member 1B. Discrepant results were obtained during the TDT analyses.The number of families available was small and for this reason we cannot conclude thatthe case-control results were spurious. We also tested the association of haplotypeswith TB. Haplotypes in the interleukin 12, beta (IL12B) and toll-like receptor 4 geneswere nominally associated with TB in both the case-control and TDT analyses. Weobserved strong LD for the genes in the South African Coloured population. In total 17novel SNPs were identified and one novel allele was found for a microsatellite inIL12B.This research contributes to the increasing amount of information available on genesinvolved in TB susceptibility, which in the future may help to predict high riskindividuals.

[发布机构] Stellenbosch University