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Polymorphismes Génétiques et Exposition au Risque Infectieux 1ère Journée de Formation Médicale Continue Outcome Réa Paris, 22 Juin 2006 Pr. Jean-Paul Mira Cochin University Hospital & Cochin Research Institute Paris, F Polymorphismes Génétiques et Réponse au Risque Infectieux 1ère Journée de Formation Médicale Continue Outcome Réa Paris, 22 Juin 2006 Pr. Jean-Paul Mira Cochin University Hospital & Cochin Research Institute Paris, F Recurrent Purpura Fulminans 2002/01: 15 yo girl admitted in ICU - Temperature 40°C; HR 125; BP 74/45; RR 38 - Meningitis with purpura fulminans - MOF (Shock, ARDS, ARF, DIC, Lactic acidosis) - Meningococcus type N in the skin biopsy - Survival with multiple finger amputations and skin grafting - 6 month hospitalization 2003/02: - Temperature 39°C; HR 125; BP 83/48; RR: 33 - Meningitis with purpura fulminans - Lumbar punction meningococcus type Y - Shock and DIC - Survival with new skin grafting - 3 month hospitalization Bohé J. Clin Infect Dis 2005 Disease Triangle P (illness) = f (host, pathogen, environment, interactions) pathogen host environment « If it were not for the great variability among individuals medicine might as well be a science and not an art » Sir William Osler, 1892 1953 2001-2003 From Watson and Crick to Human Genome 1953 Watson and Crick: double helical structure of DNA 1960s Role of RNA and Genetic Code 1970s Recombinant DNA technology 1977 Sanger and Gilbert: DNA sequencing 1983 Mapping of disorders by linkage (Huntington disease) 1986 Polymerase Chain Reaction 1990 Human Genome Project 1995 Haemophilus influenzae genome 2003 Mice and Human genome sequence Human SNP Map AS HUMANS, WE ALL SHARE THE SAME BASIC GENES BUT… Small differences in genotype make big differences to phenotype Genetic Polymorphisms Human SNP Map How SNPs Influence Human Biology Evidences for a Genetic Component to Septic Shock Animal Studies - Susceptibility/resistance to certain infection in mice - Susceptibility/resistance phenotypes of knock-out mice Intranasal challenge, 106 cfu S. pneumoniae strain D39 Intranasal challenge, 106 cfu S. pneumoniae strain D39 Fighting S. Pneumoniae: Candidate Genes ! Evidences for a Genetic Component to Septic Shock Animal Studies - Susceptibility/resistance to certain infection in mice - Susceptibility/resistance phenotypes of knockout mice Human Studies - Clinical Evidences - Ethnic Differences - Twin Studies - Adoptee Studies Incidence of Invasive Pneumococcal Disease (Age < 2 Years) Pneumococcal Bacteremia by Ethnie and Age Monroe County, New York, 1985-1989 Bennet NM; Am J Public Health 1992;82:1513 Genetic and environmental influences on premature death in adult adoptees Cause of Death (Parent Dead before the age of 50) Relative risk for the adoptee to die from the same cause All causes Biologic Adoptive 1.71 0.71 Infection Biologic Adoptive 5.8 0.73 Vascular Biologic Adoptive 4.5 3.1 Sørensen TI, et al. NEJM 1988; 318:727-32. BACTERIAL INFECTION EPITHELIAL CELLS RECEPTORS MASTOCYTE MACROPHAGE DENDRITIC CELLS IL-1 IL-12 IL-18 T LYMPHOCYTE LYMPHE NODES CHEMOKINES INFLAMMATORY CYTOKINES TNF NEURO-MEDIATORS VESSELS IFNg COAGULATION FACTORS NK CELLS PMN Genetic Polymorphisms and Septic Shock Gene Susceptibility and/or Outcome Mannose Binding Lectin Susceptibility/Mortality Toll-Like Receptor 2/4 CD14 Susceptibility Susceptibility/Mortality FCgRII Receptor Susceptibility TNF locus IL-18 IL-10 IL-6 IL-1 locus Caspase 12 Susceptibility/Mortality Susceptibility Susceptibility/Mortality Susceptibility/Mortality Susceptibility/Mortality Susceptibility PAI-1 FactorV Leiden Susceptibility/Mortality Susceptibility/Mortality IRAK-1/4 Mortality Double-stranded RNA Lipoproteins Gram+ Bacteria Fungi TLR3 TLR2 +/- TLR1/6 LPS Gram- Bacteria Monocyte or Dendritic cell Flagellin ? TLR4 TLR5 CpG DNA TLRx TLR9 NF-kB Signalisation Immunomodulatory genes Adaptative Response Tissue Injury Bacteria Lysis Cellular Immunity Apoptosis Septic Shock TLR2 and Streptococcus pneumoniae meningitis WT TLR2 -/- Echchannaoui H et al. JID 2002;186:798 TLR2 Polymorphisms in Humans Tlr2 location: Chromosome 4q32 http://www.ncbi.nlm.nih.gov/entrez/query.fcqi http://innateimmunity.net 88 SNPs • 5’UTR: 26 SNPs • 3’UTR: 17 SNPs • Intron: 29 SNPs • Exon: 16 SNPs Synonymous Non-synonymous TLR Structur Position 35 rs number 5743697 Position rs number 199 213 3804099 5743698 411(T/I) 5743699 450 3804100 e556 (I/T) 579 (R/H) 541 542 5743702 5743703 5743700 5743701 Increased susceptibility to - Mycobacterium tuberculosis Cytokine 2002;20(2):56-62 - Mycobacterium leprae J Immunol 2003;170(7):3451-4 707 781 IIPGA-TLR2-31410 5743709 631 (P/H) 677 (R/W) 5743704 5743706 715 (Y/N) 715 (Y/Amb) 753 (R/Q) 5743707 5743708 TLR2R753Q and Cytokine Production TNF-a (pg/mL) IL-10 (pg/mL) 8000 8000 6000 6000 4000 4000 2000 2000 0 0 Basal HKSA Monocytes from 8 TLR2wt Pts Basal HKSA Monocytes from 10 TLR2R753Q Pts % of patients carrying TLR2R753Q polymorphism TLR2R753Q and Septic Shock 1103 Caucasian ICU Pts (322 SS) 28 Pts TLR2R753Q (2,5%) 400 Controls ** 10.0 Microorganisms S. Pneumoniae S. aureus Candida sp. Aspergillus sp. Others 7.5 * 5.0 2.5 0 Control ICU SS G+ SS IRAK-1 Haplotype Increases NF-kB Activation IRAK-1 gene located on X chromosome 2 haplotypes: htSNP = IRAK-1 532LS Arcoli J. Am J Respir Crit Care Med 2006;175:1335 IRAK-1 Haplotype Increases Morbidity of Sepsis 155 septic Caucasians patients OR:2.6 (95% CI, 1.1-7.7) OR:2.9 (95% CI, 1.06-7.7) Arcoli J. Am J Respir Crit Care Med 2006;175:1335 IRAK-1 Haplotype Increases Mortality of Sepsis Arcoli J. Am J Respir Crit Care Med 2006;175:1335 Cytokine Polymorphisms TNF plasma levels and mortality TNF (pg/mL) Non-survivors Septic shock TNF (pg/mL) Survivors Trauma Blood Samples Martin C et al. Crit Care Med 1997;25:1813 Interindividual Differences in TNF-a Secretion TNF (pg/ml) 2500 2000 1500 1000 500 0 12,5 25 75 200 500 250000 LPS (pg/ml) Molvig, 1988 TNF locus LT-b TNF-a LT-a TNF1 TNF2 -308 -376 Nco.I TNFB1 TNFB2 Association of TNF2 with TNF levels in Septic Shock TNF1 TNF2 Appoloni O. Am J Med 2001; 110:486 TNF2 polymorphism and septic shock outcome TNF1 42.6% 39.2% TNF2 71.4% JAMA 1999;282:561-8 TNF Locus Polymorphisms and SDRA Mortality TNFA adjusted OR: 3.5; 95% CI: 1.4-8.6; p=0.007 <67 years adjusted OR: 14.9; 95% CI: 3.0-74; p<0.001 >67 years p=0.3 Gong MN Eur Respir J 2005;26:382 TNF-308 Polymorphism and Mortality of VLBW Infants 173 mechanically-ventilated very low birth weight infants Mortality 30 25 TNF1 20 TNF2 15 10 5 0 1 All Population 2 Bacteremia/Fungemia Hedberg CL. Ped Infect Dis 2004;23:424 Conclusions & Perspectives • Identification of markers of susceptibility and severity • Evaluation of the individual risk • Prevention, immunization • Pharmacogenomics • Personalized physiopathology Recurrent Purpura Fulminans 2002/01: 15 yo girl admitted in ICU - Temperature 40°C; HR 125; BP 74/45; RR 38 - Meningitis with purpura fulminans - MOF (Shock, ARDS, ARF, DIC, Lactic acidosis) - Meningococcus type N in the skin biopsy - Survival with multiple finger amputations and skin grafting - 6 month hospitalization 2003/02: - Temperature 39°C; HR 125; BP 83/48; RR: 33 - Meningitis with purpura fulminans - Lumbar punction meningococcus type Y - Shock and DIC - Survival (Xigris) with new skin grafting - 3 month hospitalization Bohé J. Clin Infect Dis 2005 Recurrent Purpura Fulminans Genetic predisposition? Innate immunity Inflammation Coagulation Innate Immunity Inflammation Coagulation TLR4 CD14 FcgRIIa FcgRIII MBL Complement C7 deficiency TNFa LTa IL-1 IL-6 IL-10 ACE Tissue Factor Prothrombin Factor V Factor VII Factor XIII PAI-1 Bohé J. Clin Infect Dis 2005 The « challenge » From Genetics to Rationale Therapeutics Conclusions & Perspectives • Identification of markers of susceptibility and severity • Evaluation of the individual risk • Prevention, immunization • Pharmacogenomics • Personalized physiopathology • Inclusion criteria in clinical trials • Interventional studies (i.e. anti-TNF) • Classification of diseases, SAPS IV, APACHE IV • Importance of phenotype+++ Conclusions & Perspectives • Identification of markers of susceptibility and severity • Evaluation of the individual risk • Prevention, immunization • Pharmacogenomics • Personalized physiopathology • Inclusion criteria in clinical trials • Interventional studies (i.e. anti-TNF) • Classification of diseases, SAPS IV, APACHE IV • Importance of phenotype+++ • Doctor’s Education and Training Genetic Polymorphisms and ICU http://geneticassociationdb.nih.gov Genetic Testing: Perspectives Genetic Testing Utility What is « tested » Benefits Risks Disease genetics Disease pronostics/diagnostics Rare Mendelian diseases; causal genes Common complex diseases; Suceptibility genes New disease insights and future medicines Pharmacogenetics Medicine response profiles Genes for drug metabolism and/or action SNP profiles for drug metabolism and/or action Optimal medicine response Potential for family/unsolicited information and ethical, legal and social implications Jean-Daniel CHICHE Christophe ROUSSEAU Joelle TEXEREAU Fatah Ouaaz Claire CHENOT Béatrice COMBA Julie TUBIANA Frédéric PENE
