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I MERCER, HEATHER MILLIKEN, DECEMBER 2013 CELL BIOLOGY the DISTRIBUTION of SINGLE NUCLEOTIDE POLYMORPHISMS in PYODERMA GANGRENO

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I MERCER, HEATHER MILLIKEN, DECEMBER 2013 CELL BIOLOGY the DISTRIBUTION of SINGLE NUCLEOTIDE POLYMORPHISMS in PYODERMA GANGRENO MERCER, HEATHER MILLIKEN, DECEMBER 2013 CELL BIOLOGY THE DISTRIBUTION OF SINGLE NUCLEOTIDE POLYMORPHISMS IN PYODERMA GANGRENOSUM: BIOMARKER DISCOVERY (124 p.) Director of Thesis: Helen Piontkivska i THE DISTRIBUTION OF SINGLE NUCLEOTIDE POLYMORPHISMS IN PYODERMA GANGRENOSUM: BIOMARKER DISCOVERY A thesis submitted To Kent State University in partial Fulfillment of the requirements for the Degree of Master of Science by Heather Milliken Mercer December 2013 ii Thesis written by Heather Milliken Mercer B.S., Kent State University, 1999 M.A., Kent State University, 2005 Approved by ___________________________________, Advisor ___________________________________, Chair, Department of Biological Sciences ___________________________________, Dean, College of Arts and Sciences iii TABLE OF CONTENTS LIST OF FIGURES……vi LIST OF TABLES……x LIST OF ABBREVIATIONS……xiii ACKNOWLEDGMENTS…………xvi CHAPTER 1: PYODERMA GANGRENOSUM, INFLAMMATION, AND APOPTOSIS…………p. 1 Hypothesis……p. 2 PG Etiology……p. 2 Multiple Pathways……p. 3 Incidence of PG……p. 4 Genetic Links to PG……p. 5 PG Clinical Variations……p. 8 Treatment of PG……p. 12 Inflammation, Apoptosis, and PG……p. 14 Errors in Apoptosis and Disease……p. 25 CHAPTER 2: METHODS…………p. 27 CHAPTER 3: RESULTS…………p. 33 CHAPTER 4: DISCUSSION…………p. 68 Significance of SNP location……p. 68 Significance of SNP state: Homozygous or Heterozygous……p. 70 PAPA Syndrome and PG SNPs in 15q24.3……p. 71 SNP_A-1874315, SNP_A-2188317, and SNP_A-2295701……p. 72 LINGO……p. 73 LOC645752……p. 74 SNP_A-1796928……p. 75 PG SNP Gene Associations, Primary Candidates, Secondary Candidates, and Master SNPs……p. 75 CASP7……p. 76 BCL2……p. 80 IL4, IL23R, IL33, IL15RA and the Interleukins……p. 82 IL15RA……p. 82 IL23R……p. 82 IL33……p. 83 IL4R……p. 84 PLCG2……p. 86 iv TABLE OF CONTENTS CONTINUED… Open Reading Frames……p. 89 The Tap Genes……p. 90 Cytochrome p450……p. 92 Selectin Genes……p. 93 Solute Carriers……p. 95 NLR’s……p. 96 “Eat me” Signals……p. 100 Colony Stimulating Factor Genes……p. 100 Limitations to this Work……p.101 Future Directions……p. 103 REFERENCES……p. 104 v LIST OF FIGURES Chapter 1: Pyoderma Gangrenosum, Inflammation, and Apoptosis Fig. 1: Co-morbidities described in 15 adults ranging from age 16-81 in association with PG (Huish et al., 2001; Rozen et al., 2001; Brunsting et al., 1930)......p. 6 Fig. 2: Co-morbidities described in children in association with PG (Data from 47 patients from Graham et al. (1994). Children’s ages ranged from 3.5-18……p. 6 Fig. 3: Ulcerative Pyoderma Gangrenosum (Bhat, 2012)......p. 9 Fig. 4: Pustular PG (Bhat, 2012)......p. 10 Fig. 5: Bullous PG (Bhat,2012)......p. 11 Fig. 6: Vegetative PG (Bhat, 2012)......p. 11 Fig. 7: The differentiation of immunity cells (Marieb, 2000)......p. 14 Fig. 8: An Overview of the Immune Response (Marieb, 2000)......p. 15 Fig. 9: The NALP3 Inflammasome (Mariathason & Monack, 2007). (ASC-apoptosis-associated speck- like protein containing a caspase-recruitment domain)......p. 22 Fig. 10: Multiple pathways leading to inflammasome assembly (Haneklaus et al., 2013)......p. 23 Chapter 2: Methods Fig. 11: Custom High Stringency Settings used in Gene Functional Classification Analysis......p. 29 Fig. 12: The NCBI Gene list is compared to the Affymetrix Immune/Inflammation Gene List......p. 29 Chapter 3: Results Fig. 13: Polymorphisms found in common among 6 PG patients are broken down and annotated with RefSeq IDs......p. 34 Fig. 14: Numbers of SNPs per presentation state (homozygous or heterozygous)......p. 35 Fig. 15: Numbers of SNPs per presentation state (homozygous or heterozygous)......p. 35 Fig. 16: Number of SNPs found in each chromosome......p. 35 vi LIST OF FIGURES CONTINUED… Chapter 3: Results Continued… Fig. 17: The PG SNP Data Set was analyzed via DAVID’s Gene Functional Classification Tool……p. 37 Fig. 18: The PG Data Set contains many dual-functioning apoptosis and immunity related gene clusters…….p. 40 Fig. 19: Number of genes within Gene Functional Classification Clusters with ES>2 related to Apoptosis/Immunity/Inflammation…….p. 41 Fig. 20: The NCBI Gene list is compared to the Affymetrix Immune/Inflammation Gene List......p. 41 Fig. 21: The AB Gene List shares 113 genes with the Affymetrix Immune/Inflammation Gene List…….p. 42 Fig. 22: The AB Gene List shares 148 genes with the NCBI Apoptosis Gene List……p. 42 Fig. 23: The AABB Gene List shares 563 genes with the NCBI Apoptosis Gene List……p. 42 Fig. 24: The AABB Gene List shares 396 genes with the Affymetrix Immune/Inflammation Gene List……p. 42 Fig. 25: The PG Gene List shares 429 genes with the Affymetrix Immune/Inflammation Gene List……p. 43 Fig. 26: The PG Gene List shares 597 genes with the NCBI Apoptosis Gene List……p. 43 Fig. 27: The AABB Gene List shares 104 genes with those shared by the NCBI Apoptosis Gene List the Affymetrix Immune/Inflammation Gene List……p. 43 Fig. 28: The AB Gene List shares 27 genes with those shared by the NCBI Apoptosis Gene List the Affymetrix Immune/Inflammation Gene List......p. 43 Fig. 29: The PG Gene List shares 111 genes with those shared by the NCBI Apoptosis Gene List the Affymetrix Immune/Inflammation Gene List……p. 43 Fig. 30: The AABB Gene List shares 751 genes with those NOT shared by the NCBI Apoptosis Gene List the Affymetrix Immune/Inflammation Gene List……p. 43 Fig. 31: The AB Gene List shares 207 genes with those NOT shared by the NCBI Apoptosis Gene List the Affymetrix Immune/Inflammation Gene List……p. 44 vii LIST OF FIGURES CONTINUED… Chapter 3: Results Continued… Fig. 32: The PG Gene List shares 804 genes with those NOT shared by the NCBI Apoptosis Gene List the Affymetrix Immune/Inflammation Gene List……p. 44 Fig. 33: The genes shared by NCBI Apoptosis and Affymetrix Immune/Inflammation Gene Lists have 111 genes in common with PG Genes and the NCBI Apoptosis List……p. 44 Fig. 34: The genes shared by NCBI Apoptosis and Affymetrix Immune/Inflammation Gene Lists have 111 genes in common with PG Genes and the NCBI Apoptosis List……p. 44 Fig. 35: A comparison of the genes shared between the PG Data Set and Immunity/Inflammation Gene List and the expected number of Immunity/Inflammation genes within the human genome……p. 45 Fig. 36: The fraction of genes shared between the PG Data Set and Apoptosis Gene List is compared with the expected number of Apoptosis genes within the human genome……p. 46 Fig. 37: The fraction of genes shared between the AABB Data Set, Apoptosis Genes and Immunity/Inflammation Genes is significantly different across comparison groups……p. 47 Fig. 38: The fraction of genes shared between the AB Data Set, Apoptosis Genes and Immunity/Inflammation Genes is significantly different across comparison groups……p. 48 Fig. 39: The genes found within the AABB Data Set show greater similarity to those shared by Apoptosis and Immunity Gene Lists than those that are not shared by the two lists......p. 49 Fig. 40: There is no significant difference between the numbers of genes shared by the AB Gene List and the AI Genes and those that are not shared……p. 50 Fig. 41: The genes found within the AABB Data Set show greater similarity to those shared by Apoptosis and Immunity Gene Lists than those that are not shared by the two lists…..p. 51 Fig. 42: PG SNPs found in common between the NCBI Apoptosis and Affymetrix Immune/Inflammation Gene Lists were further analyzed for functional relationships......p. 53 Fig. 43: A “Master” List of Apoptosis/Immunity/Inflammatory Genes was compiled and compared with the PG Gene List……p. 62 Fig. 44: PG SNPs that may cause alterations in apoptotic and inflammatory gene function possibly contributing to the PG phenotype (not a complete list)......p. 67 viii LIST OF FIGURES Chapter 4: Discussion Fig. 45: The Caspase Cascade (Sigma Aldrich, March 2013)……..p. 78 Fig. 46: The PLCG2 signaling pathway…………….p. 87 ix LIST OF TABLES Chapter 1: Pyoderma Gangrenosum, Inflammation, and Apoptosis Table 1: List of diseases which are often misdiagnosed as PG (Adapted from Bhat, 2012)......pg. 3 Table 2: Clinical Variations in PG diagnosis (Bhat, 2012)......pg. 8 Table 3: Proposed diagnostic criteria of Classic, Ulcerative Pyoderma Gangrenosum (PG). Diagnosis requires both major criteria and at least two minor criteria (Su et al., 2004)......pg. 9 Table 4: A survey of disease states associated with defects in engulfment-related genes (Adapted from Elliot & Ravichandran, 2010)......pg. 18 Table 5: A list of disorders associated with apoptotic dysfunction (Compiled by Favaloro et al., 2012)……pg. 25 Chapter 2: Methods Table 6: Lists compared utilizing MIT’s “Compare 2 Lists” online software......p. 30 Table 7: Chi2 statistical analyses of List Comparisons......p. 30 Table 8: Fisher Exact Tests performed on List Comparisons……p. 31 Chapter 3: Results Table 9: A comparison of the genes shared between the PG Data Set and Immunity/Inflammation Gene List and the expected number of Immunity/Inflammation genes in the human genome……p. 45 Table 10: The number of genes shared between the PG Data Set and Apoptosis Gene List is compared with the expected number of Apoptosis genes within the human genome......p. 46 Table 11: A comparison of Apoptosis and Immunity Genes found within the AABB Gene List......p. 47 Table 12: A comparison of Apoptosis and Immunity Genes found within the AB Gene List......p. 48 Table 13: The number of shared AI genes found within the AABB Data Set is compared to the number of A+I genes and A+I genes shared homozygously among PG patients......p. 49 x LIST OF TABLES CONTINUED… Chapter 3: Results Continued… Table 14: The number of shared AI genes found within the AB Data Set is compared to the number of A+I genes and A+I genes shared homozygously among PG patients......p.
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