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(Snps) in PTPN2/22 and Mycobacterium Avium Subspecies Paratuberculosis (MAP) in Rheumatoid Arthritis and Crohn's Disease

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(Snps) in PTPN2/22 and Mycobacterium Avium Subspecies Paratuberculosis (MAP) in Rheumatoid Arthritis and Crohn's Disease University of Central Florida STARS Electronic Theses and Dissertations, 2004-2019 2018 Role of Single Nucleotide Polymorphisms (SNPs) in PTPN2/22 and Mycobacterium Avium Subspecies Paratuberculosis (MAP) in Rheumatoid Arthritis and Crohn's Disease Robert Sharp University of Central Florida Part of the Biotechnology Commons Find similar works at: https://stars.library.ucf.edu/etd University of Central Florida Libraries http://library.ucf.edu This Doctoral Dissertation (Open Access) is brought to you for free and open access by STARS. It has been accepted for inclusion in Electronic Theses and Dissertations, 2004-2019 by an authorized administrator of STARS. For more information, please contact [email protected]. STARS Citation Sharp, Robert, "Role of Single Nucleotide Polymorphisms (SNPs) in PTPN2/22 and Mycobacterium Avium Subspecies Paratuberculosis (MAP) in Rheumatoid Arthritis and Crohn's Disease" (2018). Electronic Theses and Dissertations, 2004-2019. 6225. https://stars.library.ucf.edu/etd/6225 ROLE OF SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN PTPN2/22 AND MYCOBACTERIUM AVIUM SUBSPECIES PARATUBERCULOSIS (MAP) IN RHEUMATOID ARTHRITIS AND CROHN’S DISEASE by: ROBERT C. SHARP B.S. University of Central Florida, 2013 M.S. University of Central Florida, 2014 A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences in the Burnett School of Biomedical Sciences in the College of Medicine at the University of Central Florida Orlando, Florida Fall Term 2018 Major Professor: Saleh A. Naser © 2018 Robert C. Sharp ii ABSTRACT Both genetic pre-disposition and potential environmental triggers are shared between Rheumatoid arthritis (RA) and Crohn’s disease (CD). We hypothesized that single nucleotide polymorphisms (SNPs) in the negative T-cell regulators Protein Tyrosine Phosphatase Non- receptor type 2 and 22 (PTPN2/22) lead to a dysregulated immune response as seen in RA and CD. To test the hypothesis, peripheral leukocytes samples from 204 consented subjects were TaqMan genotyped for 9 SNPs in PTPN2/22. The SNPs effect on PTPN2/22 and IFN-y expression was determined using RT-PCR. Blood samples were analyzed for the Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene by nPCR. T-cell proliferation and response to phytohematoagglutonin (PHA) mitogen and MAP cell lysate were determined by BrdU proliferation assay. Out of 9 SNPs, SNP alleles of PTPN2:rs478582 occurred in 79% RA compared to 60% control (p-values ≤ 0.05). SNP alleles of PTPN22:rs2476601 occurred in 29% RA compared to 6% control (p-values ≤ 0.05). For the haplotype combination of PTPN2:rs478582/PTPN22rs2476601, 21.4% RA had both SNPs (C-A) compared to 2.4% control (p-values ≤ 0.05). PTPN2/22 expression in RA was decreased by an average of 1.2 fold. PTPN2:rs478582 upregulated IFN-y in RA by an average of 1.5 fold. Combined PTPN2:rs478582/PTPN22:rs2476601 increased T-cell proliferation by an average of 2.7 fold when treated with PHA. MAP DNA was detected in 34% RA compared to 8% controls (p-values ≤ 0.05), where samples with PTPN2:rs478582 and/or PTPN22:rs2476601 were more MAP positive. PTPN2:rs478582/PTPN22:rs2476601 together with MAP infection significantly increased T-cell response and IFN-y expression in RA samples. The same experimental approach was followed on blood samples from CD patients. Both PTPN2:rs478582/PTPN22:rs2476601 iii affected PTPN2/22 and IFN-y expression along with T-cell proliferation significantly more than in RA. MAP DNA was detected in 64% of CD. This is the first study to report the correlation between SNPs in PTPN2/22, IFN-y expression and MAP in autoimmune disease. iv This is dedicated to all my family and friends who have supported me throughout my entire life. Without you all, I would be nothing. Thank you. v ACKNOWLEDGMENTS I would like to thank my dad Bob Sharp for being a great role model of how a man should act, my mom Lissa Sharp for being so loving and supportive throughout my life, and Carson Sharp who is not only a great brother, but also a great friend. I would also like to thank my grandparents Nanny and Pa for their support throughout my entire college career and showing their love and support. I would like to thank my extended family and friends for their continued support throughout my life and keeping me on the right path. I also would like to thank Christine Vazquez for being there for me for both the good and the bad of my graduate career. You are the love of my life and the fire that keeps me motivated to continue to be a hard worker. I also would like to thank Dr. Saleh Naser for being a wonderful mentor and showing me how to be a great scientist, but more so, a great person. His wisdom and kindness has helped me open doors to new opportunities that I would never thought was imaginable. Thank you for turning this redneck into a full-blown scientist. I also would like to thank my dissertation committee of Dr. Griff Parks, Dr. Dinender Singla, Dr. Herve Roy and Dr. Shazia Beg. Additional thanks goes to Dr. Shazia Beg for being an integral part of our projects and for providing patient samples to us. Lastly, I would like to thank both the Florida Legislative Grant for funding our projects and both the University of Central Florida and the Burnett School of Biomedical Sciences’ Rudy J. Wodzinski Scholarship for funding me personally. vi TABLE OF CONTENTS LIST OF FIGURES ...................................................................................................................... xii LIST OF TABLES ....................................................................................................................... xiv LIST OF ACRONYMS/ABBREVIATIONS ............................................................................... xv CHAPTER ONE: INTRODUCTION ............................................................................................. 1 Autoimmune Diseases ................................................................................................................ 1 Crohn’s Disease (CD) ............................................................................................................. 1 Rheumatoid Arthritis (RA) ..................................................................................................... 2 Common Genes Associated with Autoimmune Diseases ....................................................... 3 Genetic Variations of PTPN2/22 ................................................................................................ 4 PTPN2 Role in Autoimmune Diseases ................................................................................... 4 PTPN22 Role in Autoimmune Diseases ................................................................................. 9 PTPN2/22 and Environmental Triggers in Autoimmune Diseases .......................................... 12 SNPs and Environmental Triggers Associated with Autoimmune Diseases ........................ 12 SNPs in PTPN2/22 and Infections in Autoimmune Disease ................................................ 13 Figures....................................................................................................................................... 16 References ................................................................................................................................. 18 vii CHAPTER TWO: POLYMORPHISMS IN PROTEIN TYROSINE PHOSPHATASE NON- RECEPTOR TYPE 2 AND 22 (PTPN2/22) ARE LINKED TO HYPER-PROLIFERATIVE T- CELLS AND SUSCEPTIBILITY TO MYCOBACTERIA IN RHEUMATOID ARTHRITIS .... 27 Introduction ............................................................................................................................... 27 Materials and Methods .............................................................................................................. 30 Clinical Samples ................................................................................................................... 30 Detection of MAP IS900 DNA in Peripheral Leukocytes .................................................... 35 PTPN2/22 Genotyping .......................................................................................................... 36 PTPN2/22 and IFN-γ Gene Expression ................................................................................ 37 Isolation of Peripheral Lymphocytes and Proliferation Assay ............................................. 39 Statistical Analysis ................................................................................................................ 41 Results ....................................................................................................................................... 41 Mycobacterium avium subspecies paratuberculosis IS900 DNA Detected in RA Frequency of SNP Alleles in PTPN2/22 in RA ...................................................................................... 41 Frequency of SNP Alleles in PTPN2/22 in RA .................................................................... 42 Effect of PTPN2:rs478582 and PTPN22:rs2476601 on PTPN2/22 Expression .................. 43 Effect of PTPN2:rs478582 and PTPN22:rs2476601 on T-cell Response ............................ 46 Effect of PTPN2:rs478582 and PTPN22:rs2476601 on IFN-γ Expression .......................... 48 Effect of PTPN22:rs478582 and PTPN22:rs2476601 on Susceptibility to MAP Expression ..............................................................................................................................................
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