Jorge R. Oksenberg, Ph.D. Professor of Neurology University of California, San Francisco

Jorge R. Oksenberg, Ph.D.

Professor of Neurology

University of California, San Francisco

Mapping genetic susceptibility and modeling pathogenesis in multiple sclerosis

Jorge OksenbergUCSF School of MedicineDepartment of [email protected]

Fundación Ramón Areces. Madrid, 2 de Febrero de 2012

Immune response CNS inflammation NeurodegenerationI

T cell Dendritic cell

TCR MHC

Processed Ag

CD28B7-1

IL-12

Activated CD11b+ microglia

T CELL REACTIVATION

IL-17, IL-12, IL-23, OPNchemokines

IFN-, IL-2

Cytokines and

chemokines

M Y E L I N

Activation of NA+ channels and reverse Na+Ca2+ exchange

Ca2+ Na+

excess glutamate

ROS

AutoantibodiesComplement

Immune response

CNS inflammation

NeurodegenerationII

DCT

T

M

a

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

Multiple Sclerosis

MS is a complex genetic disease

Genome-wide association screens MS

Study DesignPopulation

origin

Number of screened samples

Number of SNPs

Featured loci / genes

Wellcome Trust CCC (2007)

Cases-shared controls

UK1,000 cases

1,500 controls14,436 (non

synonymous)IL7R

IMSGC (2007)Family and case

controlUS, UK 931 family trios 334,923

HLA, IL2R, IL7R, CLEC16, CD58,

EVI5, TYK2

Comabella et al. (2008)

Pooled case-control

Spain242 cases

242 controls 500,000 HLA, 13q31.3

GeneMSA C. (2009)

Case-controlUS, The

Netherlands, Switzerland

978 cases 883 controls

551,642HLA, GPC5,

PDZRNA4, CSMD1

ANZ C. (2009)Case-shared

controlsAustralia and New Zealand

1,618 cases 3,413 controls

303,431HLA, METTL1,

CD40

De Jager et al. (2009)

Meta-analysis and case-

control

US, UK, The Netherlands, Switzerland

2,624 case 7,220 controls

2,557,248 (imputed)

TNFRSF1A, IRF8, CD6, RGS1

Jakkula et al. (2010)

Isolated case-control

Finland68 cases

136 controls297,343 STAT3

Sanna et al. (2010)

Case-control Sardinia882 cases

872 controls6,600,000 (imputed)

HLA, CBLB

IMSGC (2011) Case-control US, Europe, Australia

9,772 cases 17,376 controls

441,547 HLA, 29 novel

IMSGC & WTCCC2 Nature (2011) 476; 214-9

The MS Genome 2012

IMSGC & WTCCC2 Nature (2011) 476; 214-9

Genome-wide significant

Discovery P < 10-4.5 and consistent replication

Discovery P < 10-3

MS susceptibility genes in the T helper cell differentiation pathway

The autoimmunity web

Baranzini S. Curr Opin Immunol 21:596, 2009

Pathways and networks in MS

Filtered GWAS nominal association P-values overlap with a PPI network

GOID GOTerm GOLevels GOGroupNr.

Genes% Associated

Genes Term PValue

GO:0007411 axon guidance [4, 5, 7, 8, 9, 10, 11, 12] [None] 23 6.571429 1.84E-08

GO:0002755MyD88-dependent toll-like receptor signaling pathway [7, 8, 9, 10, 11, 12] [Group9] 7 9.459459 2.16E-04

GO:0034142 toll-like receptor 4 signaling pathway [7, 8, 9, 10, 11, 12] [Group9] 7 8.641975 3.79E-04

GO:0002756MyD88-independent toll-like receptor signaling pathway [7, 8, 9, 10, 11, 12] [Group9] 6 9.230769 6.99E-04

GO:0042093 T-helper cell differentiation [9, 10, 11, 12, 13]

[Group1, Group24, Group28] 4 16 6.99E-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

GO:0007193inhibition of adenylate cyclase activity by G-protein signaling pathway

[7, 8, 9, 10, 11, 12, 13, 14, 15] [Group23] 4 9.302325 0.005410457

Baranzini et al. Hum Molec Genet 18:2078, 2009

Cumulative genetic risk

MSGB gradient in multi- and single-case families


MSGB gradient among siblings


No direct use in diagnosticNo predictive power

MSGB gradient among siblings

MS makes its first clear appearance in 1822 in the diaries of Augustus D’Este, the illegitimate grandson of King George III (Firth D, 1948)

Sir Augustus d’Este (1794-1848) from the collection of the Victoria and Albert Museum, London.

Full-genome sequencing of a multi-case MS family

I

II

III

DRB1*15:01 DRB1*15:01

DRB1*15:01 DRB1*15:01 DRB1*15:01

DRB1*15:01


Input: 4.5 million variants (SNVs and indels) / genome

L. Madireddy, P. Khankhanian & S. Baranzini


Chr Pos Gene symbol Description

chr1:150727539 CTSS Cathepsin S

chr10:115393929 NRAP Nebulin-related anchoring protein

chr10:88414569 OPN4 Opsin 4

chr11:134128923 ACAD8 Acyl-CoA dehydrogenase family, member 8

chr4:84383735 FAM175A Family with sequence similarity 175, member A

chr5:55206444 IL31RA Interleukin 31 receptor A

chr7:142630534 TRPV5 Transient receptor potential cation channel, subfamily V5

chr7:149473614 SSPO SCO-spondin homolog

chr7:47851623 PKD1L1 Polycystic kidney disease 1 like 1

chr3:111921116 SLC9A10 Solute carrier family 9, member 10



chr4:126237567 FAT4 FAT tumor suppressor homolog 4

Gene discovery in MS

A/A

G/G

A/G

First reportedassociation

betweenMS and HLA

STUDIES

GENES

1972

HLA

Meta-analysisof GWAS

2009

CD226CD6IRF8

TNFRSF1ATYK2

First generationGWAS

(1000 patients)

2007

VCAMPLEKMERTSP140

EOMESCD86IL12B

BACH2THEMIS

MYBIL22RA2TAGAPZNF767

MYCPVT1HHEX

CLECL1ZFP36L1

BATFGALCMALT1

TNFSF14MPV17L2

DKKL1MAPK1SCO2

NFKB2CXCR5SOX8

RPS6KB1TNFRSF6CYP27B1CYP24A1

Whole genomesequencingof MS twins

2010

Second generationGWAS (10,000 patients)

First generation genome-wide linkage studies (400 markers)

1996

Second generation genome-wide linkage study (5000 markers)

2005

MMEL1RGS1

KIF21BCBLB

TMEM39AIL12A

PTGEROLIG3

IL7ZMIZ1

MPHOSPH9STAT3CD40

IL2RAIL7RCD58

CLEC16AEVI5

2011

Treatment of Multiple SclerosisHarrison’s Principles of Internal Medicine 3rd Ed, 1958

The most that can be done is to reassure and encourage the patient through moderate exercise and supportive measures…during an acute episode it is surely preferable to assure the patient that he will recover and to preserve silence on the subject of relapse.

John N. Walton

Multiple Sclerosis

Interferons

Phase I

Phase II

Phase III

Marketed

Anti-proliferationagents

im IFN β-1a

Atacicept

AlemtuzumabRituximab

Novantrone

sc IFN β-1a

sc IFN β-1b

Teriflunomide

Natalizumab

DaclizumabPixantrone

Targeted mAbs/Fc-Ab

Cladribine

Fingolimod

Azathioprine

oral administration

injectable

Riluzole

Symptomatic Tx

Vaccine, tolerization

Anti-T cell vaccine

ATL-1102

MM-093BG12

AJM-300

Nerispirdine

IFNTauIFN omega

Peg IFN (BIIB017)

Fc- IF

ATX-MS-1467

Firategrast

Ofatumumab

Delta-9-THC

Lymphocyte trafficking

TBC4746

MLN-0002

Targeted Immune

regulationPI2301

R1295

Glatiramer acetate

Laquinimod

Fampridine SR

683699 (T-0047)

Ocrelizumab

LY-2127399

Courtesy of Gavin Giovannoni

Multiple Sclerosis therapeutics 2012

• 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.

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.


• 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.

The convergence of -omics with next generation imaging, informatics, and effective Electronic Medical Record systems will:


Front-end tablet Application

Database Gateway & Computations

Reference groups of patientsIndividual data

User data Imaging

Documents

Jorge R. Oksenberg, Ph.D. Professor of Neurology University of California, San Francisco