Endometriosis gene-expression, meta-analysis

1,138 views
1,054 views

Published on

Higher order of endometriosis gene-expression, chromosome 1q significantly contributes to endometriosis specific gene-expression, meta-analysis of three (3)independent endometriosis studies

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
1,138
On SlideShare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
12
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Endometriosis gene-expression, meta-analysis

  1. 1. Gene-expression in Endometriosis: Chromosome 1q significantly contributes to endometriosis gene-expression<br />MehisPold, M.D.<br />Founder<br />EOMIX, Inc.<br />August 9, 2010<br />8/9/2010<br />1<br />mehis.pold@eomix.com<br />
  2. 2. Endometriosis (from endo, "inside", and metra, "womb") is a medical condition in which endometrial cells are deposited in areas outside the uterine cavity. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones. Endometrial cells deposited in areas outside the uterus (endometriosis) continue to be influenced by these hormonal changes and respond similarly as do those cells found inside the uterus. Symptoms often exacerbate in time with the menstrual cycle.<br />Endometriosis is typically seen during the reproductive years; it has been estimated that it occurs in roughly 5% to 10% of women. Symptoms depend on the site of implantation. Its main but not universal symptom is pelvic pain in various manifestations. Endometriosis is a common finding in women with infertility.<br />Source: Wikipedia<br />Terms:<br />Ectoendometrium – endometrial tissue outside of it’s natural location<br />Euendometrium – endometrium in it’s natural location, uterine cavity<br />8/9/2010<br />2<br />mehis.pold@eomix.com<br />
  3. 3. Diagnostics of Endometriosis:<br />INVASIVE - Confirmed by laparoscopy<br />Exclusion of other conditions<br />Systemic diagnostic markers poorly understood<br />Medical need for non-invasive diagnostic test<br />How do we find endometriosis markers?<br />Blood<br />Urine<br />Saliva<br />Skin biopsy<br />Hair follicles<br />8/9/2010<br />3<br />mehis.pold@eomix.com<br />
  4. 4. (1) Meta-analysis of three independent whole-genome expression sets<br />(2) GenMAPP pathway analysis<br />Endometriosis database of EOMIX Inc.<br />8/9/2010<br />4<br />mehis.pold@eomix.com<br />
  5. 5. Summary Statistics of Endometriosis sets (Roth, Klinkova, Hull)<br />Pathway analysis by GenMAPP on genes altered in at least two of out three Endometriosis datasets<br />N = 2,522 = Venn diagram [2+3+4]<br />R = 19,632<br />8/9/2010<br />5<br />mehis.pold@eomix.com<br />
  6. 6. GenMAPP calculates hypergeometric distribution<br />GenMAPP is a freeware<br />Mathematics of hypergeometric distribution<br />R – depends on cut-offs: e.g. p-value < 0.01<br />n – specific MAPP  pathway<br />Produces best results when<br /><ul><li> R  10 – 15% of N
  7. 7. n  is not too small or too large</li></ul>Excellent software but beware of mathematical limitations!<br />Results depend on Gene Ontology hierarchies and the existing pathway information<br />Many genes have no GO annotations and positions on currently known pathways<br />Z-values greater than 2 and smaller than -2 considered relevant<br /><ul><li> Z < -2 and Z > 2</li></ul>8/9/2010<br />6<br />mehis.pold@eomix.com<br />
  8. 8. GenMAPP Overview<br />Small amount of information does not produce reliable results<br />Results depend on Gene Ontology hierarchies and the existing pathway information<br />Z-values greater than 2 and smaller than -2 considered relevant<br /> Z < -2 and Z > 2<br />Examples at R/N= 0.128 (12.8%)<br />n = 90 pathway of 90 known members,<br />r = 30 of which 30 are altered<br />r/n = 0.333 (33.3%)<br />Z = 5.82<br />n = 9<br />r = 3<br />r/n = 0.333 (33.3%)<br />Z = 1.83 = insignificant<br />8/9/2010<br />7<br />mehis.pold@eomix.com<br />
  9. 9. GenMAPP pathways upregulatedin endometriosis<br />GenMAPP pathways Gene Ontology Samples KEGG converted<br />Nicotinate and nicotinamide metabolism<br />Biological Processes<br /><ul><li>Actin cytoskeleton organization and biogenesis
  10. 10. Actin filament-based process
  11. 11. Anion transport
  12. 12. Cell growth
  13. 13. Cell-cell adhesion
  14. 14. Endocytosis
  15. 15. Enzyme-linked receptor protein signaling
  16. 16. Growth
  17. 17. Humoral Defense sensu Vertebrata
  18. 18. Humoral Immune response
  19. 19. I-kappa kinase NF-kappa cascade
  20. 20. Inflammatory response
  21. 21. Inorganic anion transport
  22. 22. Muscle contraction
  23. 23. Muscle development
  24. 24. Regulation of cell size
  25. 25. Transmembrane receptor PTK signaling</li></ul>Cellular Component<br /><ul><li>Actin cytoskeleton
  26. 26. Cytoskeleton
  27. 27. Extracellular matrix sensuMetazoa
  28. 28. Plasma membrane</li></ul>Molecular Function<br /><ul><li>Actin binding
  29. 29. Carbohydrate binding
  30. 30. Enzyme activator activity
  31. 31. Enzyme inhibiting activity
  32. 32. GTPase activator activity</li></ul>Cellular Processes<br /><ul><li> Focal adhesion
  33. 33. G13 signalin
  34. 34. G-protein signaling
  35. 35. Integrin-mediated adhesion
  36. 36. T -cell receptor pathway</li></ul>Metabolic Processes<br /><ul><li>Prostaglandin synthesis</li></ul>Molecular Function<br /><ul><li> Small ligand GPCR</li></ul>Physiological Process<br /><ul><li>Adipogenesis
  37. 37. Calcium regulation in cardiac muscle
  38. 38. Circadian exercise
  39. 39. Complement activation by classical pathway
  40. 40. Complement and coagulation cascade KEGG
  41. 41. Smooth muscle contraction
  42. 42. Striated muscle contraction</li></ul>8/9/2010<br />8<br />mehis.pold@eomix.com<br />
  43. 43. GenMAPP pathways downregulated in endometriosis<br />GenMAPP pathways Gene Ontology Samples KEGG converted<br /><ul><li>Biotin metabolism
  44. 44. Glutathione metabolism
  45. 45. Lysine biosynhesis
  46. 46. Lysine degradation
  47. 47. Methionine metabolism
  48. 48. Nicotinate and nicotinamide metabolism
  49. 49. One carbon pool by folate
  50. 50. Phe, Tyr, Trp biosynthesis
  51. 51. Selenoamina acid metabolism
  52. 52. Sphingoglycolipid metabolism</li></ul>Biological Processes<br /><ul><li> Cell cycle
  53. 53. Cytokinesis
  54. 54. DNA repair
  55. 55. DNA replication
  56. 56. M phase
  57. 57. M phase of mitotic cell cycle
  58. 58. Microtubule-based process
  59. 59. Regulation of cell cycle
  60. 60. Response to DNA damage stimuli
  61. 61. Response to endogenous stimuli</li></ul>Cellular Component<br /><ul><li> Chromatin
  62. 62. Endomembrane system
  63. 63. Microtubule cytoskeleton</li></ul>Molecular Function<br /><ul><li> Ligase activity
  64. 64. Nucleotidyltrasferase activity
  65. 65. Protein transporter activity</li></ul>Cellular Processes<br /><ul><li> Androgen receptor pathway
  66. 66. Cell cycle G1 to S control
  67. 67. Delta-Notch signaling
  68. 68. DNA replication reactome
  69. 69. Hedgehog pathway
  70. 70. mRNA processing reactome
  71. 71. TNFalpha-NFkB pathway</li></ul>Metabolic Processes<br /><ul><li> Electronic transport chain
  72. 72. Fatty acid synthesis
  73. 73. Nucleotide metabolism</li></ul>Molecular Function<br /><ul><li> Homologous recombination
  74. 74. Mismatch repair</li></ul>Physiological Process<br />8/9/2010<br />9<br />mehis.pold@eomix.com<br />
  75. 75. Endometriosis pathway analysis summary<br /><ul><li>Inflammation and immune response upregulated in endometriosis: complement, inflammation mediators, humoral response, T-cell response, B-cell receptor genes
  76. 76. Muscle-related pathways upregulated in endometriosis: smooth and striated muscle-related genes, calcium-regulated gene-expression.
  77. 77. Cytoskeleton-related processes involved
  78. 78. Metabolism and Cell cycle appear low in endometriosis as compared to normal endometrial tissue</li></ul>Connection to previously published studies<br />Plasma cell infiltration ~ high levels of B-cell receptor gene-expression documented in previous studies. Heveret al. (PNAS, 2007) documented plasma-cell infiltration of ovarian endometriosis.<br />8/9/2010<br />10<br />mehis.pold@eomix.com<br />
  79. 79. Chromosome 1q produces substantial levels of endometriosis-specific gene-expression<br />8/9/2010<br />11<br />mehis.pold@eomix.com<br />
  80. 80. Chromosome 1q32 genes that exhibit altered expression in endometriosis<br />Red font and blue font denote up- and downregulation, respectively<br />8/9/2010<br />12<br />mehis.pold@eomix.com<br />
  81. 81. SUMMARY<br />Pathways modulating host defense are activated in endometriosis<br /> Chromosome 1q significantly contributes to endometriosis gene-expression<br />8/9/2010<br />mehis.pold@eomix.com<br />13<br />

×