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Exploring Tuberculosis Genetics

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Exploring Tuberculosis Genetics EXPLORING TUBERCULOSIS GENETICS: RESISTANCE TO INFECTION, PROGRESSION TO ACTIVE DISEASE, HOST GENETICS AND MYCOBACTERIUM TUBERCULOSIS LINEAGES WITHIN A HOUSEHOLD CONTACT STUDY IN KAMPALA, UGANDA. by NOÉMI BORSAY HALL Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Department of Epidemiology and Biostatistics CASE WESTERN RESERVE UNIVERSITY May 2016 1 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the dissertation of Noémi Borsay Hall candidate for the degree of Doctor of Philosophy* Committee Chair Catherine M. Stein, Ph.D. Committee Member W. Henry Boom, M.D. Committee Member Rob P. Igo, Jr., Ph.D. Committee Member Nathan J. Morris, Ph.D. Date of Defense March 16, 2016 *We also certify that written approval has been obtained for any proprietary material contained therein 2 Dedication This work is dedicated to my family, especially Rev. Dr. Daniel J. Borsay, Dr. Rudy Almasy, the late Dr. A. Wahab Khair and the late Rev. Dr. Laszlo A. Borsay. Emma Rose- have you started thinking about your dissertation topic yet? 3 Table of Contents Dedication ........................................................................................................................................ 2 Table of Contents ............................................................................................................................. 3 List of Tables .................................................................................................................................... 5 List of Figures ................................................................................................................................... 6 Acknowledgements.......................................................................................................................... 7 List of Commonly Used Abbreviations ............................................................................................. 9 Chapter 1: Introduction ................................................................................................................. 13 Specific Aims .............................................................................................................................. 14 Specific Aim 1: ........................................................................................................................ 14 Specific Aim 2: ........................................................................................................................ 15 Specific Aim 3: ........................................................................................................................ 15 Chapter 2: Background and Literature Review .............................................................................. 16 2.1 Epidemiology of TB .............................................................................................................. 16 2.2 The RSTR Phenotype ............................................................................................................ 21 2.3 Genetic Associations with TB ............................................................................................... 22 2.4 Genetic Associations with RSTR ........................................................................................... 27 2.5 SNP Annotation Databases .................................................................................................. 30 2.6 Mycobacterium tuberculosis and host immune response ................................................... 32 2.7 Mycobacterium tuberculosis Lineage .................................................................................. 36 Chapter 3: Candidate Gene Analysis .............................................................................................. 39 3.1 Introduction ......................................................................................................................... 39 3.2 Study population .................................................................................................................. 39 3.3 Candidate gene genotyping ................................................................................................. 40 3.4 Statistical Analysis ................................................................................................................ 41 3.5 Validation Analysis ............................................................................................................... 42 3.6 Initial Results ........................................................................................................................ 43 Genetic association with TB ................................................................................................... 43 Genetic association with RSTR ............................................................................................... 44 3.7 Validation Results ................................................................................................................ 46 Genetic association with TB ................................................................................................... 46 Genetic association with RSTR ............................................................................................... 46 4 3.8 Meta-Analysis....................................................................................................................... 47 Meta-Analysis with TB ........................................................................................................... 47 Meta-Analysis with RSTR ....................................................................................................... 47 3.9 Discussion............................................................................................................................. 53 Chapter 4: RSTR and Annotated SNP Selection ............................................................................. 60 4.1 Introduction ......................................................................................................................... 60 4.2 Study population .................................................................................................................. 60 4.3 SNP Selection ....................................................................................................................... 61 4.4 Statistical Analysis ................................................................................................................ 63 4.5 Results .................................................................................................................................. 65 4.6 Discussion............................................................................................................................. 69 4.7 Gene Level Analysis .............................................................................................................. 73 4.8 Results .................................................................................................................................. 73 4.9 Conclusions .......................................................................................................................... 77 Chapter 5: SEM and IFNγ Immune Response ................................................................................ 80 5.1 Introduction ......................................................................................................................... 80 5.2 Study population .................................................................................................................. 80 5.3 Human Genotyping .............................................................................................................. 80 5.4 Immunological Data ............................................................................................................. 81 5.5 Mtb Genotyping ................................................................................................................... 81 5.6 Structural Equation Modeling .............................................................................................. 82 5.7 Statistical Analysis ................................................................................................................ 83 5.8 Structural Equation Modeling Results ................................................................................. 87 5.9 Discussion............................................................................................................................. 91 Chapter 6: Discussion and Conclusions ......................................................................................... 96 Appendix A ………………………………...………………………………………………………………………………………… 101 Bibliography ................................................................................................................................. 102 5 List of Tables Table 1. IFNγ Response and Mtb Lineage Preliminary Data .......................................................... 38 Table 2. Illumina 10k Initial Analysis and Omni5 Validation Sample characteristics .................... 45 Table 3. Results of genetic association analysis validation of TB phenotype ............................... 48 Table 4. Results of genetic association analysis validation of RSTR phenotype ........................... 50 Table 5. Comparison of Illumina 10k Initial Analysis and Omni5 Validation Sample characteristics, by phenotype .......................................................................................................
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