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Title page for ETD etd-04102015-120032


Type of Document Dissertation
Author Sobota, Rafal Sebastian
Author's Email Address rafal4484@gmail.com
URN etd-04102015-120032
Title Genetics of Tuberculosis Resistance
Degree PhD
Department Human Genetics
Advisory Committee
Advisor Name Title
Bingshan Li Committee Co-Chair
Dana C. Crawford Committee Co-Chair
Carl H. Johnson Committee Member
Jonathan L. Haines Committee Member
Luc Van Kaer Committee Member
Scott M. Williams Committee Member
Keywords
  • il9
  • tuberculosis
  • il12b
  • gwas
Date of Defense 2015-04-01
Availability unrestricted
Abstract
One third of the world’s 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.

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