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WP 6.3 Genomics and chronic inflammation

WP 6.3 Genomics and chronic inflammation. 9 th Consortium Meeting, Rome , 14-15 September 2006. SYSTEMIC EFFECTS OF PERIODONTITIS AND ASSOCIATION WITH CARDIOVASCULAR DISEASES. Rome: 14 Sept 2006. Marja L. Laine & Bruno G. Loos. Kristina Hettne & Scott Boyer. Marc Weeber.

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WP 6.3 Genomics and chronic inflammation

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  1. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 SYSTEMIC EFFECTS OF PERIODONTITIS AND ASSOCIATION WITH CARDIOVASCULAR DISEASES Rome: 14 Sept 2006 Marja L. Laine & Bruno G. Loos Kristina Hettne & Scott Boyer Marc Weeber

  2. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 Presentation Outline • Introduction Periodontitis – Atherosclerosis • Methods • TextBLAST • Results • PathwayAssist • Results • Discussion

  3. WP 6.3 Genomics and chronic inflammation osteoporosis mortality diabetes pulmonary infections premature low birth weight cardiovascular diseases subclinical atherosclerosis 9th Consortium Meeting, Rome, 14-15 September 2006 THE PERIO – SYSTEMIC CONNECTION epidemiological studies – periodontitis as independent risk factor

  4. WP 6.3 Genomics and chronic inflammation Relation atherosclerosis and periodontitis Dental plaque Fibrous plaques Chronic inflammation in coronary arteries Chronic inflammation in periodontium • Bacteraemia • Increased inflammatory • activity Atherosclerotic lesion Periodontitis 9th Consortium Meeting, Rome, 14-15 September 2006

  5. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 How could there be a relation between atherosclerosis and periodontitis? TextBlast PathwayAssist

  6. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 TextBLAST • Database of concept profiles or ‘fingerprints’ derived from PubMed • Search on gene or disease • Get matching genes, Gene Ontology terms, pathways, and diseases • We focused on genes

  7. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 Creating Document Profiles Thesauri Document profiles or ‘fingerprints’ Document set Text Indexer

  8. WP 6.3 Genomics and chronic inflammation ESR1 estrogen receptor 1 breast neoplasm 0.5 BRCA1 0.34 PGR 0.30 Estrogen 0.28 BRCA2 0.25 TP53 0.15 gene suppressor tumor 0.12 genetics polymorphism 0.12 genetic predisposition to disease 0.10 female 0.05 9th Consortium Meeting, Rome, 14-15 September 2006 Creating Concept Profiles Aggregate fingerprints per concept: Fingerprints Concept profile Aggregation

  9. WP 6.3 Genomics and chronic inflammation Compute distances between concepts Find concepts related to your concept of interest 9th Consortium Meeting, Rome, 14-15 September 2006 What can you do with concept profiles?

  10. Gene Symbol Gene Full Name % Similarity WP 6.3 Genomics and chronic inflammation PON1 Paraoxonase 1 100 CD14 CD14 antigen 85 TLR2 Toll-like receptor 2 71 ADIPOQ Adiponectin, C1Q and collagen domain containing 66 PON2 Paraoxonase 2 56 TLR4 Toll-like receptor 4 48 OLR1 Oxidised low density lipoprotein (lectin-like) receptor 1 48 MTHFR 5,10-methylenetetrahydrofolate reductase (NADPH) 47 CXCL16 Chemokine (C-X-C motif) ligand 16 45 9th Consortium Meeting, Rome, 14-15 September 2006 SCARB1 Scavenger receptor class B, member 1 43 TNFRSF11B Tumor necrosis factor receptor superfamily, member 11b (osteoprotegerin) 40 FCGR2A Fc fragment of IgG, low affinity IIa, receptor (CD32) 40 CXCL10 Chemokine (C-X-C motif) ligand 10 36 ADD1 Adducin 1 alpha 32 CCR2 Chemokine (C-C motif) receptor 2 32 APOE Apolipoprotein E 30 TextBLAST Results

  11. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 TextBLAST Results Summary • 7 (CD14, TLR2, ADIPOQ, TLR4, MTHFR, FCGR2A, APOE) out of the 16 genes have previously been suggested as links between periodontitis and atherosclerosis • 3 genes (TNFRSF11B, CXCL10, CCR2) have been investigated in both diseases but never before been suggested to link them together • 6 genes (PON1, PON2, OLR1, CXCL16, SCARB1, ADD1) have previously only been linked to atherosclerosis but not periodontitis

  12. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 PathwayAssist • Database of interactions between entities (e.g. proteins, small molecules) derived from literature • Visualisation of the interactions • Pathways

  13. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 Direct Interactions Network

  14. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 PathwayAssist Results Summary 1 • LPS directly regulates CXCL10, OLR1, CCR2, CD14, TLR2, TLR4, FCGR2A, SCARB1, and APOE • Manual PubMed search added PON1, TNFRSF11B, ADIPOQ, and CXCL16 to the list of genes regulated by LPS • ADD1 was found to be regulated by Lipoarabinomannan, which is structurally similar to LPS

  15. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 Direct Interactions, Including Intermediate Nodes

  16. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 PathwayAssist Results Summary 2 • New intermediate nodes: • IL8 – suggested before to link periodontitis and atherosclerosis • LBP – suggested before to link periodontitis and atherosclerosis • STAT1 – suggested to be involved in atherosclerosis but has not been mentioned together with periodontitis • All of the above interact with LPS

  17. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 General Points for Discussion • Using PathwayAsssist to investigate how the output genes from TextBLAST are connected could be a way of validating the gene hit list • Why were not all interactions between the proteins in the hit list and LPS found by PathwayAssist? - Implications • Interestingly, CRP and IL-6 were not in the top 30% of genes. • Is inflammation triggered by LPS the common factor?

  18. WP 6.3 Genomics and chronic inflammation 9th Consortium Meeting, Rome, 14-15 September 2006 Manuscript in Preparation Finding Links between Periodontitis and Atherosclerosis in the Literature: a Combination of Co-Occurrence and Natural Language Processing Techniques Kristina M. Hettne, Marja Laine, Scott Boyer, Marc Weeber, Bruno G. Loos

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