One third of the worlds population has been infected with Mycobacterium tuberculosis (MTB). Most of those exposed develop an asymptomatic latent infection. In the absence of co-morbidities, only 5-10% of people progress to active tuberculosis disease (TB) post-exposure, defined as primary TB. However, immunosuppression resulting from malnutrition or human immunodeficiency virus (HIV) co-infection increases the likelihood of both primary TB and activation of a latent infection. As a result, tuberculosis remains a major global health problem. Worldwide, TB is the second-leading cause of mortality from a single infectious agent, after HIV. In 2013, 9 million new cases of clinical tuberculosis were diagnosed and 1.5 million deaths were attributed to the disease. An estimated 360,000 deaths occurred in people co-infected with HIV, and 75% of these cases occurred in sub-Saharan Africa.
MTB infection and tuberculosis disease have a substantial heritable component. In this project, we studied a genetic resistance phenotype to TB disease and MTB infection, as opposed to more standard approaches tailored towards finding loci associated with susceptibility. We recruited HIV-positive patients from three recently concluded prospective cohorts of TB from Uganda and Tanzania. We hypothesized that HIV-positive individuals living in MTB hyperendemic areas who do not develop TB disease represent an extreme resistance phenotype. A study of 175,906 variants in 267 cases and 314 controls revealed a genome-wide significant association of a common TB resistance single nucleotide polymorphism, rs4921437, in the regulatory region of IL12, a gene previously associated with susceptibility. We also hypothesized that HIV-positive individuals who do not establish MTB infection despite living in hyperendemic regions are genetically resistant. In a study of 162,228 variants in 244 cases and 235 controls, we discovered a genome-wide significant association of a resistance variant rs877356 near IL9, a gene previously associated with bronchial hyperresponsiveness and asthma. Furthermore, we evaluated the effects of multi-locus interactions in a candidate gene approach and found that epistasis also plays a significant role in risk of MTB infection and TB disease.
We present a novel approach to genome-wide association studies, also applicable to whole genome sequencing studies, where the use of an extreme resistance phenotype allowed us to identify large effect sizes and attain genome-wide significance in cohorts of a relatively small sample size. The use of HIV status as a central feature of our hypothesis as opposed to a confounder or exclusion criterion is also unique.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-04102015-120032 |
| Date | 13 April 2015 |
| Creators | Sobota, Rafal Sebastian |
| Contributors | Scott M. Williams, Dana C. Crawford, Jonathan L. Haines, Luc Van Kaer, Bingshan Li, Carl H. Johnson |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-04102015-120032/ |
| Rights | restrictsix, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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