Genetics of susceptibility to tuberculosis

Awomoyi, Agnes Abiola Oluwatoyin (2000). Genetics of susceptibility to tuberculosis. PhD thesis The Open University.



Convincing evidence that activated macrophages play a critical role in control of mycobacterial diseases has been clearly established from animal and in-vitro studies. Macrophages produce a variety of molecules upon appropriate stimulation, which act in concert towards eventual killing of bacteria. People with SUb-optimal macrophage activation are more susceptible to infection with intracellular pathogens. My project aims to answer two questions relating to genetic regulation of macrophage activation in tuberculosis: do macrophage genes regulate microbial-induced responses and do macrophage genes influence susceptibility to tuberculosis? A whole blood assay was used to investigate IFN-y responsiveness in healthy individuals and those who develop tuberculosis in The Gambia. Cytokine responses to lipopolysaccaride (LPS), Lipoarabinomanan (LAM) and the enhancing effect of IFN-y on these stimulants were measured. LPS induced IL-l 0 levels was higher in recovered TB cases than in controls (p=0.02). LPS and LAM induced cytokines were highly correlated (p<0.0001) similarly, levels of IL-1β and TNF were highly correlated (P<0.0001). Ten new polymorphisms were detected by sequencing specific regions within the promoter of IFNG and IFNGR1 genes. One, a double deletion of TT in the promoter of IFNGR1, abolishes a GAS binding site at position -470 and another, a C/T transition, is close to a putative NF-kappa β binding site at position -56 in the IFNGR1 gene (positions are relative to the transcription start site). These along with published polymorphisms at some macrophage candidate gene loci were genotyped. Comparisons were made to determine whether different alleles at candidate gene loci influence macrophage cytokine responses. TNFA-863, LTA Nco1 lL1RN and NRAMP1 (469+14) polymorphisms were shown to influence macrophage cytokine levels significantly. TNFA-863 was associated with LPS induced TNF (P< 0.05), LTA was associated with LAM and LPS induced TNF and IL- β levels (p< 0.01). NRAMP1 (469+14) was associated with LAM induced 1L-10 (P< 0.01) and IL1RN was associated with LAM and LPS induced IL-10 (P<0.05).

Alleles 1 (G) of TNFA-308, 2 (A) of TNFA-238, 1 (T) of IL1B-511 and 2 (ddel/T) of IFNGR1 were significantly associated with TB in the panel of samples studied. For the microsatellite markers, allele 5 of IL9 (TG)n repeat in intron 4 and allele 3 of the Z DNA promoter polymorphism NRAMP1, were significantly associated with TB.

NRAMP1 INT4 variant was significantly associated with both TB and LAM induced IL-10 secretion.

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