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Interleukin 12P40 genetic polymorphisms and tuberculosis in Chinese|[electronic resource]

by Tso, Hoi-wan

Abstract (Summary)
(Uncorrected OCR) iii

Abstract of thesis entitled

Interleukin 12P40 Genetic Polymorphisms and Tuberculosis in Chinese

submitted by TsoHoi Wan

for the Degree of Master of Philosophy at the University of Hong Kong

in August 2003

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis. It has re-emerged as a leading global health problem accounting for 8.7 million new cases and 1.7 million deaths every year. The imperative role of host genetic factors in TB susceptibility is inferred by 10% of infected individuals developing clinical disease, higher disease concordance in monozygotic than dizygotic twins and differential infection rates among racial groups.

Interleukin 12 (IL-12) is a heterodimer cytokine produced by antigen-presenting cells which induces the proliferation and cytolytic activity of T cells and the production of interferon gamma (IFN-D). It is composed of two subunits, p35 and p40, which are encoded by genes on chromosome 3 and 5 respectively. IL-12P40 gene polymorphisms have been reported at the promoter, intron 2, intron 4, exon 5 and 3' untranslated region (UTR). The vital role of1L-12 in regulating T helper type

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1 (Thl) response and cell-mediated immunity against TB is illustrated by murine knockout models and by patients with inherited immunodeficiency predisposing to mycobacterial infections. IL-12 deficient mice are more susceptible to mycobacterial infection than wild type mice. In humans, complete IL-12p40 deficiency is due to rare mutations in the IL-12P40 gene.

Since IL-12 is a key protective Thl cytokine against mycobacterial infection, we hypothesized that genetic polymorphisms in IL-12P40 may contribute to TB susceptibility. To test the hypothesis, we first investigated the association between the five reported IL-12P40 polymorphisms and TB in 516 patients and 514 healthy controls. Second, we carried out functional analysis to correlate the associated polymorphisms with IL-12p70 protein level.

After multiple logistic regression analysis, our results showed that individuals homozygous for allele 1 at intron 2 of IL-12P40 had a 2.l4-fold increased risk of developing TB (P < 0.001; 95% CI, 1.45-3.19). Haplotype frequency was estimated and two risk haplotypes A (p=0.0250) and K (p=0.0001) and two protective haplotypes B (0.0058) and G (p=0.017) were found. We next analyzed all polymorphisms and generated diplotypes. Diplotype I, likely composed of haplotype A and K, was only observed in the TB patients (n=25; P < 0.0001) and was found to be associated with the development of extrapulmonary TB (P = 0.0136; OR, 3.5; 95% CI, 1.34-8.81). On the contrary, diplotype II composed of homozygous haplotype B occurred at a significantly higher frequency in the controls (11.6%) than in the patients (6.4%) (P = 0.0091; OR, 0.56; 95% CI, 0.35-0.90). Individuals who were haplotype B carriers (n=57; mean, 430?82pg/ml) expressed higher IL-12p70

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protein level than non-carriers (n=41; mean, 375?17pg/ml).

In summary, genotype 1/1 at intron 2 of IL-12P40 represents a disease susceptibility locus for TB. Individuals with diplotype I (haplotypes A and K) are at increased risk of developing TB disease and extrapulmonary TB In contrast, diplotype II (haplotype B) confers protective effect against TB.

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Bibliographical Information:

Advisor:

School:The University of Hong Kong

School Location:China - Hong Kong SAR

Source Type:Master's Thesis

Keywords:university of hong kong dissertations interleukin 12 genetic polymorphisms

ISBN:

Date of Publication:01/01/2004

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