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Creando el mapa de la susceptibilidad genética y un modelo de patogénesis en esclerosis múltiple
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Creando el mapa de la susceptibilidad genética y un modelo de patogénesis en esclerosis múltiple



Ciclo de conferencias y debates en Ciencias. ...

Ciclo de conferencias y debates en Ciencias.

Fundación Ramón Areces-Nature Publishing Group.

Jorge R. Oksenberg. Universidad de California, San Francisco, EE. UU.

Madrid, 2 de febrero de 2012



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Creando el mapa de la susceptibilidad genética y un modelo de patogénesis en esclerosis múltiple Presentation Transcript

  • 1. Mapping genetic susceptibility and modeling pathogenesis in multiple sclerosis Fundación Ramón Areces. Madrid, 2 de Febrero de 2012Jorge OksenbergUCSF School of MedicineDepartment of Neurology Jorge R. Oksenberg, Ph.D.jorge.oksenberg@ucsf.edu Professor of Neurology University of California, San Francisco
  • 2. I Immune response CNS inflammation Neurodegeneration Processed Ag T CELL excess REACTIVATION glutamate Autoantibodies TCR MHC Cytokines Complement and chemokines ROS IL-17, IL-12, IL-23, OPN chemokines MYELIN CD28B7-1 Activated Ca2+ Na+T cell Dendritic IFN-, IL-2 CD11b+ microglia cell Activation of NA+ channels and IL-12 reverse Na+Ca2+ exchange a T T DC M II Immune response Neurodegeneration CNS inflammation
  • 3. Multiple Sclerosis 1:1000 in North Americans and Europeans Incidence increased steadily during the 20th century F:M ratio = 2-3:1 Age of onset = 20-40 Influence of latitude on risk Influence of ancestry on risk Disease family history in ~20% of cases
  • 4. MS is a complex genetic disease
  • 5. Genome-wide association screens MS Number of Population Number of Featured loci / Study Design screened origin SNPs genes samplesWellcome Trust Cases-shared 1,000 cases 14,436 (non UK IL7RCCC (2007) controls 1,500 controls synonymous) HLA, IL2R, IL7R, Family andIMSGC (2007) US, UK 931 family trios 334,923 CLEC16, CD58, case control EVI5, TYK2Comabella et al. Pooled case- 242 cases Spain 500,000 HLA, 13q31.3(2008) control 242 controls US, TheGeneMSA C. 978 cases HLA, GPC5, Case-control Netherlands, 551,642(2009) 883 controls PDZRNA4, CSMD1 Switzerland Case-shared Australia and 1,618 cases HLA, METTL1,ANZ C. (2009) 303,431 controls New Zealand 3,413 controls CD40 Meta-analysis US, UK, TheDe Jager et al. 2,624 case 2,557,248 TNFRSF1A, IRF8, and case- Netherlands,(2009) 7,220 controls (imputed) CD6, RGS1 control SwitzerlandJakkula et al. Isolated case- 68 cases Finland 297,343 STAT3(2010) control 136 controlsSanna et al. 882 cases 6,600,000 Case-control Sardinia HLA, CBLB(2010) 872 controls (imputed)IMSGC (2011) Case-control US, Europe, 9,772 cases 441,547 HLA, 29 novel Australia 17,376 controls
  • 6. The MS Genome 2012 IMSGC & WTCCC2 Nature (2011) 476; 214-9
  • 7. MS susceptibility genes in the T helper cell differentiation pathwayGenome-wide significantDiscovery P < 10-4.5 and consistent replicationDiscovery P < 10-3 IMSGC & WTCCC2 Nature (2011) 476; 214-9
  • 8. The autoimmunity webBaranzini S. Curr OpinImmunol 21:596, 2009
  • 9. Pathways and networks in MS Nr. % Associated GOID GOTerm GOLevels GOGroup Genes Genes Term PValue GO:0007411 axon guidance [4, 5, 7, 8, 9, 10, 11, 12] [None] 23 6.571429 1.84E-08 MyD88-dependent toll-like receptor signaling Filtered GWAS GO:0002755 pathway [7, 8, 9, 10, 11, 12] [Group9] 7 9.459459 2.16E-04 nominal GO:0034142 toll-like receptor 4 signaling pathway [7, 8, 9, 10, 11, 12] [Group9] 7 8.641975 3.79E-04 association P- MyD88-independent toll-like receptor signaling GO:0002756 pathway [7, 8, 9, 10, 11, 12] [Group9] 6 9.230769 6.99E-04 values overlap [Group1, with a PPI Group24, GO:0042093 T-helper cell differentiation [9, 10, 11, 12, 13] Group28] 4 16 6.99E-04 network GO:0034138 toll-like receptor 3 signaling pathway [7, 8, 9, 10, 11, 12] [Group9] 6 8.955224 8.21E-04 GO:0034130 toll-like receptor 1 signaling pathway [7, 8, 9, 10, 11, 12] [Group9] 6 8.695652 9.60E-04 GO:0034134 toll-like receptor 2 signaling pathway [7, 8, 9, 10, 11, 12] [Group9] 6 8.450705 0.001116036 GO:0031290 retinal ganglion cell axon guidance [5, 6, 8, 9, 10, 11, 12, 13] [None] 3 20 0.001749115 inhibition of adenylate cyclase activity by G- [7, 8, 9, 10, 11, 12, 13, 14, GO:0007193 protein signaling pathway 15] [Group23] 4 9.302325 0.005410457Baranzini et al. Hum Molec Genet18:2078, 2009
  • 10. Cumulative genetic risk MSGB gradient in multi- and single-case families
  • 11. Cumulative genetic risk MSGB gradient among siblings
  • 12. Cumulative genetic riskMSGB gradient among siblings No direct use in diagnostic No predictive power
  • 13. Sir Augustus d’Este (1794-1848) from the collection of the Victoria and Albert Museum, London.MS makes its first clear appearance in 1822 in the diaries of AugustusD’Este, the illegitimate grandson of King George III (Firth D, 1948)
  • 14. Full-genome sequencing of a multi-case MS family DRB1*15:01I DRB1*15:01 DRB1*15:01IIIII DRB1*15:01 DRB1*15:01 DRB1*15:01
  • 15. Full-genome sequencing of a multi-caseMS family Input: 4.5 million variants (SNVs and indels) / genome L. Madireddy, P. Khankhanian & S. Baranzini
  • 16. Full-genome sequencing of a multi-case MS family Chr Pos Gene symbol Descriptionchr1:150727539 CTSS Cathepsin Schr10:115393929 NRAP Nebulin-related anchoring proteinchr10:88414569 OPN4 Opsin 4chr11:134128923 ACAD8 Acyl-CoA dehydrogenase family, member 8chr4:84383735 FAM175A Family with sequence similarity 175, member Achr5:55206444 IL31RA Interleukin 31 receptor A Transient receptor potential cation channel, subfamilychr7:142630534 TRPV5 V5chr7:149473614 SSPO SCO-spondin homologchr7:47851623 PKD1L1 Polycystic kidney disease 1 like 1chr3:111921116 SLC9A10 Solute carrier family 9, member 10chr3:111962851 SLC9A10 Solute carrier family 9, member 10chr3:111996554 SLC9A10 Solute carrier family 9, member 10chr4:126237567 FAT4 FAT tumor suppressor homolog 4
  • 17. Gene discovery in MS Second generation Second generation GWAS (10,000 patients) genome-wide linkage study (5000 markers) Whole genome First generation sequencing genome-wide linkage of MS twins First reported studies (400 markers) association First generation between GWAS Meta-analysis MS and HLA (1000 patients) of GWAS STUDIES 1972 1996 2005 2007 2009 2010 2011A/A GENESG/G HLA IL2RA CD226 MMEL1 IL7R CD6 RGS1 VCAM CLECL1 CD58 IRF8 KIF21B PLEK ZFP36L1A/G CLEC16A TNFRSF1A CBLB MERT BATF EVI5 TYK2 TMEM39A SP140 GALC IL12A MALT1 EOMES PTGER TNFSF14 CD86 OLIG3 MPV17L2 IL12B IL7 DKKL1 BACH2 ZMIZ1 MAPK1 THEMIS MPHOSPH9 SCO2 MYB STAT3 NFKB2 IL22RA2 CD40 CXCR5 TAGAP ZNF767 SOX8 MYC RPS6KB1 PVT1 TNFRSF6 HHEX CYP27B1 CYP24A1
  • 18. Multiple Sclerosis Treatment of Multiple Sclerosis Harrison’s Principles of Internal Medicine 3rd Ed, 1958The most that can be done is to reassure andencourage the patient through moderate exercise andsupportive measures…during an acute episode it issurely preferable to assure the patient that he willrecover and to preserve silence on the subject ofrelapse. John N. Walton
  • 19. Multiple Sclerosis therapeutics 2012 Phase I Lymphocyte AJM-300 trafficking Phase II Interferons Fc- IFb ATL-1102 TBC4746 IFN omega Phase III Firategrast IFNTau R1295 Marketed Fingolimod MLN-0002 Peg IFNb sc IFN β-1b Natalizumab (BIIB017) im IFN β- sc IFN β- 1a Laquinimod 1a Azathioprine Riluzole Novantrone Anti-proliferation Cladribine agents Teriflunomide Daclizuma Glatiramer b Pixantrone acetate BG12 MM-093 Anti-T cell Delta-9-THC vaccine 683699 (T-0047) ATX-MS-1467 Targeted Immune Fampridine SR regulation Rituximab Alemtuzumab Vaccine, PI2301 Nerispirdine tolerization Ocrelizumab LY-2127399 Atacicept Symptomatic Tx Ofatumumaboral administration Targetedinjectable mAbs/Fc-Ab Courtesy of Gavin Giovannoni
  • 20. MS as a genetic disease. The agenda• In the last 10 years, sequencing technologies have improved by many orders of magnitude.• In the last 5 years, tissue and organ imaging technologies permit the (non-invasive) deconstruction of the phenotype to the metabolite level.
  • 21. MS as a genetic disease. The agenda• Advances in microscopy now make it possible to observe how individual cells, including neurons behave when genes are turned on and off.• Cell- and molecular- resolution models of the nervous system is looking more and more doable.• Major improvements in the development of systems and network-based approaches for the interpretation of high-dimensional biological data.
  • 22. MS as a genetic disease. The agendaThe convergence of -omics with next generationimaging, informatics, and effective ElectronicMedical Record systems will:• Allow the deployment of this information in a point-of-care decision support environment.• Generate a genetic road map to guide us in the discovery of new drugs at an unprecedented pace.• Allow to implement the promise of personalized medicine.
  • 23. Database Gateway Front-end tablet & Computations ApplicationUser data Imaging ReferenceIndividual data groups of patients