endometriosis gene-expression, meta-analysis
DESCRIPTION
Higher order of endometriosis gene-expression, chromosome 1q significantly contributes to endometriosis specific gene-expression, meta-analysis of three (3)independent endometriosis studiesTRANSCRIPT
Gene-expression in Endometriosis: Chromosome 1q significantly
contributes to endometriosis gene-expression
Mehis Pold, M.D.Founder
EOMIX, Inc.
August 9, 2010
04/12/2023 [email protected]
Terms:
Ectoendometrium – endometrial tissue outside of it’s natural locationEuendometrium – endometrium in it’s natural location, uterine cavity
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.
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.
Source: Wikipedia
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Diagnostics of Endometriosis:
INVASIVE - Confirmed by laparoscopyExclusion of other conditions
Systemic diagnostic markers poorly understood
Medical need for non-invasive diagnostic test
How do we find endometriosis markers?
BloodUrineSaliva
Skin biopsyHair follicles
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Exper
Platf
GEO Platform
IDAuthors
Non-disease Endometrium
Endometriosis Summary
GSE7305
Affy
GPL570 Roth et al. 10 10 Normal and diseased (ovarian endometriosis) human tissues w ere profiled for gene expression
GSE7846
Affymetr
GPL570 Sha et al. 5 5
The pathogenesis of endometriosis may result from aberrant angiogenesis that occurs in eutopic
endometrium w ith retrograde menstruation. The difference in gene expression profile betw een human
endometrial endothelial cells (HEECs) from eutopic endometria
GSE5108
GE Hea
GPL2895 Klinkova et al. 11 11
Experimental design: Eutopic and ectopic endometrium w ere obtained from the same patients; for each
patient, eutopic endometrium from the uterus served as the control for her ectopic endometrial samples.
GSE6364
Affymet
GPL570 Burney et al. 16 21
Analysis of endometrial specimens from w omen w ith endometriosis. Endometrial gene expression examined
at various phases of the menstrual cycle. Results provide insight into the molecular pathogenesis of
endometriosis.
GSE4888
Affymet
GPL570 Talbi et al. 27
Analysis of the normal endometrium at distinct phases of the menstrual cycle. Results provide insight into w hether molecular profiles of the endometrium can
distinguish the different phases of the menstrual cycle.
GSE12446
Affyme
GPL570 Klaassens et al. 31
Transcriptome analysis of human endometrial tissues from healthy post-menoupausal w omen reflecting the
endometrial response to 3-w eeks treatment w ith tibolone, E2 and E2+MPA.
GSE11769
Affymetr
GPL96 Hull et al. 9 9
The pathophysiology of endometriotic lesion development remains unclear but involves a complex interaction betw een ectopic endometrium and host
peritoneal tissues.
Endometriosis database of EOMIX Inc.
(1) Meta-analysis of three independent whole-genome expression sets(2) GenMAPP pathway analysis
04/12/2023 [email protected]
Roth
Klinkova
Hull
Pathway analysis by GenMAPP on genes altered in at least two of out three Endometriosis datasets
N = 2,522 = Venn diagram [2+3+4]R = 19,632
Summary Statistics of Endometriosis sets (Roth, Klinkova, Hull)
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Variable Value
N 19,632
R 2,522
n 25
r 7
Z 2.265788
Mathematics of hypergeometric distribution
R – depends on cut-offs: e.g. p-value < 0.01n – specific MAPP pathway
Produces best results when• R 10 – 15% of N• n is not too small or too large
Excellent software but beware of mathematical limitations!
Results depend on Gene Ontology hierarchies and the existing pathway information
Many genes have no GO annotations and positions on currently known pathways
Z-values greater than 2 and smaller than -2 considered relevant• Z < -2 and Z > 2
GenMAPP calculates hypergeometric distributionGenMAPP is a freeware
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Variable Value
N 19,632
R 2,522
n 90
r 30
Z 5.82174
Results depend on Gene Ontology hierarchies and the existing pathway information
Z-values greater than 2 and smaller than -2 considered relevant
Z < -2 and Z > 2
Examples at R/N= 0.128 (12.8%)
n = 90 pathway of 90 known members,r = 30 of which 30 are altered
r/n = 0.333 (33.3%)Z = 5.82
n = 9r = 3r/n = 0.333 (33.3%)Z = 1.83 = insignificant
GenMAPP OverviewSmall amount of information does not produce reliable results
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GenMAPP pathways upregulated in endometriosisGenMAPP pathways Gene Ontology Samples KEGG converted
Cellular Processes• Focal adhesion• G13 signalin• G-protein signaling• Integrin-mediated adhesion• T -cell receptor pathway
Metabolic Processes• Prostaglandin synthesis
Molecular Function• Small ligand GPCR
Physiological Process• Adipogenesis• Calcium regulation in cardiac muscle• Circadian exercise• Complement activation by classical
pathway• Complement and coagulation cascade
KEGG• Smooth muscle contraction• Striated muscle contraction
Biological Processes• Actin cytoskeleton organization and
biogenesis• Actin filament-based process• Anion transport• Cell growth• Cell-cell adhesion• Endocytosis• Enzyme-linked receptor protein
signaling• Growth• Humoral Defense sensu Vertebrata• Humoral Immune response• I-kappa kinase NF-kappa cascade• Inflammatory response• Inorganic anion transport• Muscle contraction• Muscle development• Regulation of cell size• Transmembrane receptor PTK
signaling
Cellular Component• Actin cytoskeleton• Cytoskeleton• Extracellular matrix sensu Metazoa• Plasma membrane
Molecular Function• Actin binding• Carbohydrate binding• Enzyme activator activity• Enzyme inhibiting activity• GTPase activator activity
Nicotinate and nicotinamide metabolism
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GenMAPP pathways Gene Ontology Samples KEGG converted
Cellular Processes• Androgen receptor pathway• Cell cycle G1 to S control• Delta-Notch signaling• DNA replication reactome• Hedgehog pathway• mRNA processing reactome• TNFalpha-NFkB pathway
Metabolic Processes• Electronic transport chain• Fatty acid synthesis• Nucleotide metabolism
Molecular Function• Homologous recombination• Mismatch repair
Physiological Process
Biological Processes• Cell cycle• Cytokinesis• DNA repair• DNA replication• M phase• M phase of mitotic cell cycle• Microtubule-based process• Regulation of cell cycle• Response to DNA damage stimuli• Response to endogenous stimuli
Cellular Component• Chromatin• Endomembrane system• Microtubule cytoskeleton
Molecular Function• Ligase activity• Nucleotidyltrasferase activity• Protein transporter activity
• Biotin metabolism• Glutathione metabolism• Lysine biosynhesis• Lysine degradation• Methionine metabolism• Nicotinate and nicotinamide
metabolism• One carbon pool by folate• Phe, Tyr, Trp biosynthesis• Selenoamina acid
metabolism• Sphingoglycolipid
metabolism
GenMAPP pathways downregulated in endometriosis
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Endometriosis pathway analysis summary
• Inflammation and immune response upregulated in endometriosis: complement, inflammation
mediators, humoral response, T-cell response, B-cell receptor genes
• Muscle-related pathways upregulated in endometriosis: smooth and striated muscle-related
genes, calcium-regulated gene-expression.
• Cytoskeleton-related processes involved
• Metabolism and Cell cycle appear low in endometriosis as compared to normal endometrial
tissue
Connection to previously published studies
Plasma cell infiltration ~ high levels of B-cell receptor gene-expression documented in previous studies. Hever et al.
(PNAS, 2007) documented plasma-cell infiltration of ovarian endometriosis.
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Variable Value
N 19,632
R 2,522
n 104
r 23
Z 2.8324
1q21Variable Value Variable Value
N 19,632 N 19,632
R 2,522 R 2,522
n 681 n 895
r 115 r 145
Z 3.207 Z 3.0701
1q21-1q32 1q12-1q44
Chromosome 1q produces substantial levels of endometriosis-specific gene-expression
Variable Value
N 19,632
R 2,522
n 156
r 32
Z 2.8731
1q32
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Gene Name Gene Symbol Chromosomal locus
feline leukemia virus subgroup C cellular receptor 1 FLVCR1 chr1q32.3denticleless homolog (Drosophila) DTL chr1q32.1-q32.2TNF receptor-associated factor 5 TRAF5 chr1q32interferon regulatory factor 6 IRF6 chr1q32.3-q41TRAF3 interacting protein 3 TRAF3IP3 chr1q32.3-q41plexin A2 PLXNA2 chr1q32.2complement component (3b/4b) receptor 1 (Knops blood group) CR1 chr1q32complement component 4 binding protein, beta C4BPB chr1q32interleukin 10 I L10 chr1q31-q32SLIT-ROBO Rho GTPase activating protein 2 SRGAP2 chr1q32.1chromosome 1 open reading frame 186 C1orf186 chr1q32.1solute carrier family 41, member 1 SLC41A1 chr1q32.1RAB7, member RAS oncogene family-like 1 RAB7L1 chr1q32hypothetical protein LOC284576 LOC284576 chr1q32.1neurofascin homolog (chicken) NFASC chr1q32.1leucine rich repeat neuronal 2 LRRN2 chr1q32.1phosphoinositide-3-kinase, class 2, beta polypeptide PIK3C2B chr1q32pleckstrin homology domain containing, family A member 6 PLEKHA6 chr1q32.1golgi transport 1 homolog A (S. cerevisiae) GOLT1A chr1q32.1proline/arginine-rich end leucine-rich repeat protein PRELP chr1q32fibromodulin FMOD chr1q32jumonji, AT rich interactive domain 1B J ARID1B chr1q32.1protein phosphatase 1, regulatory (inhibitor) subunit 12B PPP1R12B chr1q32.1ubiquitin-conjugating enzyme E2T (putative) UBE2T chr1q32.1E74-like factor 3 (ets domain transcription factor, epithelial-specific ) ELF3 chr1q32.2leiomodin 1 (smooth muscle) LMOD1 chr1q32cysteine and glycine-rich protein 1 CSRP1 chr1q32kinesin family member 14 KIF14 chr1q32.1protein tyrosine phosphatase, receptor type, C PTPRC chr1q31-q32NIMA (never in mitosis gene a)-related kinase 7 NEK7 chr1q31.3asp (abnormal spindle) homolog, microcephaly associated (Drosophila) ASPM chr1q31complement factor H CFH chr1q32
UP in ECTO vs. EU
Down in ECTO vs. EU
Chromosome 1q32 genes that exhibit altered expression in endometriosis
Red font and blue font denote up- and downregulation, respectively
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SUMMARY
Pathways modulating host defense are activated in endometriosis
Chromosome 1q significantly contributes to endometriosis gene-expression