Date of Award

January 2016

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Richard Bucala

Abstract

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays an important role in the pathogenesis of autoimmune inflammatory diseases. Functional promoter variants in the MIF gene influence host susceptibility to different infectious diseases, including tuberculosis (TB). However, the effect of functional MIF promoter variants in subjects with co-infection with human immunodeficiency virus (HIV) and TB, who comprise over 12 percent of new TB cases globally and 60 percent of new TB cases in South Africa, has been examined only in one prior study. Here, an association study was carried out in a clinically well-defined rural population in KwaZulu-Natal, South Africa to evaluate the influence on tuberculosis of two MIF promoter polymorphisms: a MIF -794 CATT5-8 microsatellite (rs5844572) and a -173 G/C single nucleotide polymorphism (SNP)(rs755622). A higher number of CATT microsatellite repeats results in increased MIF expression, and there is prior evidence that the -173 C allele is in linkage disequilibrium with the high expresser -794 CATT7 allele.

Patients with active tuberculosis (n = 120) and unrelated controls (n = 144) were examined in the pulmonary TB portion of the study. These groups were further stratified based on HIV status and TB disease state: active, latent infection, or negative for infection. Controls were classified as being positive or negative for latent TB infection using an Elispot assay (IFNγ ELISpot). In subjects with the clinical complication of TB meningitis, HIV positive patients with TB meningitis (n=48) and unrelated controls presenting with non-TB meningitis (n=130) were studied. TB meningitis was diagnosed either with culture or polymerase chain reaction (PCR).

Analysis revealed that the low expresser MIF -794 CATT5+6 alleles were associated with TB disease in the HIV positive groups (OR = 3.09, 95% CI = 1.42 – 6.74, P = 0.004). There was no significant association of MIF -173 alleles with TB disease in either HIV positive or HIV negative groups. There was no significant difference in the two alleles between control subjects with latent TB compared to those negative for TB infection. Serum MIF levels were measured for a subset of samples (n=208) and revealed elevated levels in those with TB disease compared to those without TB disease, both between groups with HIV infection (P=0.01) and between groups without HIV infection (P=0.01). In the meningitis cohorts, genetic analysis revealed no association between the MIF -794 CATT5+6 alleles and TB meningitis. However, the low expresser MIF -173 G allele was associated with TB meningitis when studied in comparison to patients with other forms of meningitis (OR = 1.79, 95% CI = 1.11 – 2.90, P = 0.017).

These results indicate that polymorphisms in the promoter of the MIF gene are not associated with acquisition of TB infection. However, once subjects are infected with Mycobacterium tuberculosis, low expresser MIF alleles confer risk for the development of TB disease, including meningitis. Additionally, there is an interaction between these susceptibility alleles and co-infection with HIV. Given that the highest global population incidence of low genotypic MIF expressers occurs in South Africa, these data support an important role for the MIF locus in the development of severe TB.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 08/24/2018

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