Download D_Oliver

Genes, Drugs, and Diseases
for a Pharmacogenetics
Knowledge Base
Diane E. Oliver, MD, PhD
Stanford University
SOFG – Nov. 19, 2002
Outline
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Pharmacogenetics and PharmGKB
Sources of genes, drugs, and diseases
Representation of concepts
Maintenance
Summary
Outline
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Pharmacogenetics and PharmGKB
Sources of genes, drugs, and diseases
Representation of concepts
Maintenance
Summary
Pharmacogenetics
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Pharmacogenetics = the science of how genes
influence an individual’s response to drugs
Gene–drug association
( Gene
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Drug )
Adverse Effect
6-mercaptopurine + TPMT
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Fatal bone marrow suppression
Pre-prescription genetic testing
Adverse Effect
Response
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Efficacy
Efficacy
Codeine + CYP2D6
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7-10% of Caucasians
poor metabolizers
No effect on pain
Research in Pharmacogenetics
CYP2D6, CYP2C19, CYP3A5
SLC6A4 (SERT)
Tamoxifen
Adverse Effects:
Hot flashes,
cholesterol,
clotting
Efficacy (Asthma):
Responders or
nonresponders
Flunisolide
NR3C1 (GR)
Paroxetine
Enzymes
Transporters
?
Receptors
Ion Channels
Efficacy (Depression):
Responders or
nonresponders
Adverse Effects:
Torsades de
pointes,
long QT syndrome
Quinidine
SCN5A, KCNH2
Research in Pharmacogenetics
CYP2D6, CYP2C19, CYP3A5
SLC6A4 (SERT)
Tamoxifen
Adverse Effects:
Hot flashes,
cholesterol,
clotting factors
Efficacy (Asthma):
Responders or
nonresponders
Flunisolide
NR3C1 (GR)
Paroxetine
Enzymes
Transporters
?
Receptors
Ion Channels
Efficacy (Depression):
Responders or
nonresponders
Adverse Effects:
Torsades de
pointes,
long QT syndrome
Quinidine
SCN5A, KCNH2
Research in Pharmacogenetics
CYP2D6, CYP2C19, CYP3A5
SLC6A4 (SERT)
Tamoxifen
Adverse Effects:
Hot flashes,
cholesterol,
clotting factors
Efficacy (Asthma):
Responders or
nonresponders
Flunisolide
NR3C1 (GR)
Paroxetine
Enzymes
Transporters
?
Receptors
Ion Channels
Efficacy (Depression):
Responders or
nonresponders
Adverse Effects:
Torsades de
pointes,
long QT syndrome
Quinidine
SCN5A, KCNH2
Research in Pharmacogenetics
CYP2D6, CYP2C19, CYP3A5
SLC6A4 (SERT)
Tamoxifen
Adverse Effects:
Hot flashes,
cholesterol,
clotting factors
Efficacy (Asthma):
Responders or
nonresponders
Flunisolide
NR3C1 (GR)
Paroxetine
Enzymes
Transporters
?
Receptors
Ion Channels
Efficacy (Depression):
Responders or
nonresponders
Adverse Effects:
Torsades de
pointes,
long QT syndrome
Quinidine
SCN5A, KCNH2
Research in Pharmacogenetics
CYP2D6, CYP2C19, CYP3A5
SLC6A4 (SERT)
Tamoxifen
Adverse Effects:
Hot flashes,
cholesterol,
clotting factors
Efficacy (Asthma):
Responders or
nonresponders
Flunisolide
NR3C1 (GR)
Paroxetine
Enzymes
Transporters
?
Receptors
Ion Channels
Efficacy (Depression):
Responders or
nonresponders
Adverse Effects:
Torsades de
pointes,
long QT syndrome
Quinidine
SCN5A, KCNH2
PharmGKB
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What is PharmGKB?
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Goals of PharmGKB (the project)
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A project
A web site http://pharmgkb.org
A knowledge base
A team
To collect pharmacogenetic data and knowledge in a
centralized repository
To provide a public resource
To facilitate and catalyze research in pharmacogenetics
Informatics topics: ontologies, knowledge representation
Outline
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Pharmacogenetics and PharmGKB
Sources of genes, drugs, and diseases
Representation of concepts
Maintenance
Summary
Sources of
Genes, Drugs, and Diseases
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Goals
Leverage off the work of others
 Coordinate with national and international communities
 Maintainable
 Locally extensible
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Concept Type
Genes
Drugs
Diseases
Sources
HGNC, LocusLink
NDF-RT, Orange Book
MeSH
Sources of Concepts
HGNC
LocusLink
NDF-RT
Orange Book
PharmGKB
Gene, Drug, Disease
Terminologies
MeSH
Gene Source - HGNC
HUGO
Gene Nomenclature Committee
Approved Gene Name
ATP-binding cassette, subfamily B (MDR/TAP), member 1
Approved Gene Symbol ABCB1
Previous Symbol
PGY1, MDR1
Aliases
P-gp
Previous Gene Name
LocusLink ID
5243
http://www.gene.ucl.ac.uk/public-files/nomen/searchdata.txt
Gene Source - LocusLink
LocusLinkID
5243
Alternate symbols
MDR1, P-gp, PGY1, ABC20, GP170
Aliases
multidrug resistance 1
Cytogenetic location 7q21.1
OMIM phenotype
Colchicine resistance
Gene category (GO) ATP binding, transporter
Genbank accession AC002457, AF016534, M29422
RefSeq NT, NP, NM NM_000927, NP_000918
http://www.ncbi.nlm.nih.gov/LocusLink
Drug Source – NDF-RT
<conceptDef>
<name>ASPIRIN 325MG TAB [NDC: 00839676409]</name>
<namespace>NDF</namespace>
<primitive/>
<kind>DRUG_KIND</kind>
<name>
<definingConcepts>
<concept>ASPIRIN 325MG TAB</concept>
</definingConcepts>
<definingRoles>
</definingRoles>
<properties>
<property>
<name>NDF_Trade_Name</name>
<value>ASPIRIN 325MG TABLET</value>
</property>
<property>
<name>PackageSize</name>
<value>250</value>
</property>
<property>
<name>PackageType</name>
<value>BOTTLE</value>
</property>
<property>
<name>Manufacturer</name>
<value>H L MOORE DRUG</value>
</property>
</properties>
</conceptDef>
ASPIRIN 325MG TAB [NDC: 00839676409] </name>
<kind>DRUG_KIND</kind>
<concept>ASPIRIN 325MG TAB</concept>
<name>NDF_Trade_Name</name>
<value>ASPIRIN 325MG TABLET</value>
<name>PackageSize</name>
<value>250</value>
<name>PackageType</name>
<value>BOTTLE</value>
<name>Manufacturer</name>
<value>H L MOORE DRUG</value>
Drug Source – Orange Book
PROCAINAMIDE HYDROCHLORIDE~Capsule;
Oral~PRONESTYL~APOTHECON~250MG~007335~001~AB~Approved prior to Jan
1, 1982~No~RX
DICYCLOMINE HYDROCHLORIDE~Capsule; Oral~BENTYL~AVENTIS
PHARMS~10MG~007409~003~AB~OCT 15, 1984~Yes~RX
NOREPINEPHRINE BITARTRATE~Injectable; Injection~LEVOPHED~ABBOTT~EQ
1MG BASE/ML~007513~001~~Approved prior to Jan 1, 1982~Yes~RX
METHIMAZOLE~Tablet; Oral~TAPAZOLE~LILLY~5MG~007517~002~AB~Approved
prior to Jan 1, 1982~No~RX
ASPIRIN~Tablet, Extended Release; Oral~8-HOUR BAYER
~BAYER~650MG~016030~001~~Approved prior to Jan 1, 1982~No~DISCN
HYDROCORTISONE~Tablet; Oral~CORTEF~PHARMACIA AND
UPJOHN~10MG~008697~001~BP~Appro
WARFARIN SODIUM~Tablet; Oral~COUMADIN~BRISTOL MYERS
SQUIBB~10MG~009218~005~AB~Approved prior to Jan 1, 1982~Yes~RXved prior
to Jan 1, 1982~Yes~RX
Disease Source - MeSH
*NEWRECORD
RECTYPE = D
MH = Asthma
AQ = BL CF CI CL CN CO DH DI DT EC EH EM EN EP ET GE HI IM ME MI MO NU
PA PC PP PS PX RA RH RI RT SU TH UR US VE VI
PRINT ENTRY = Asthma, Bronchial|T047|NON|EQV|UNK (19XX)|840210|abcdef
PRINT ENTRY = Bronchial Asthma|T047|NON|EQV|UNK (19XX)|840210|abcdef
ENTRY = Asthmas
ENTRY = Asthmas, Bronchial
ENTRY = Bronchial Asthmas
MN = C08.127.108
MN = C08.381.495.108
MN = C08.674.095
MN = C20.543.480.680.095
FX = Anti-Asthmatic Agents
MH_TH = NLM (1966)
MS = A form of bronchial disorder associated with airway obstruction,
marked by recurrent attacks of paroxysmal dyspnea, with wheezing due to
spasmodic contraction of the bronchi.
Outline
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Pharmacogenetics and PharmGKB
Sources of genes, drugs, and diseases
Representation of concepts
Maintenance
Summary
Representation of Concepts
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Two approaches
KB = Knowledge base
 DB = Relational database
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KB implementation
http://protege.stanford.edu
Protégé: Frame-based knowledge representation system
 Frames and slots – hierarchies, links among concepts
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DB implementation
Oracle: Relational database management system
 Tables and columns – indexed lookups, joins
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Representation of Concepts
Relational DB
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Table Names
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Genes
Gene Symbols
Gene Synonyms
GeneID
Gene OMIM Phenotypes
Gene Products
Gene Golden Path Sequence
Drugs
DrugID
Drug Synonyms
Diseases
DiseaseID
Disease Synonyms
Outline
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Pharmacogenetics and PharmGKB
Sources of genes, drugs, and diseases
Representation of concepts
Maintenance
Summary
Maintenance of PharmGKB Data
HGNC
LocusLink
VA-NDF
Orange Book
PharmGKB
Gene, Drug, Disease
Terminologies
ValidFrom
ValidTo
01-01-2000
MeSH
PharmGKB
Archive
ValidFrom
ValidTo
01-01-2000
03-04-2002
Maintenance of Concepts
HGNC
LocusLink
VA-NDF
Orange Book
PharmGKB
local additions
Gene, Drug, Disease
Terminologies
MeSH
PharmGKB
Archive
Outline
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Pharmacogenetics and PharmGKB
Sources of genes, drugs, and diseases
Representation of concepts
Maintenance
Summary
Summary
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Controlled terminologies essential for indexing and
querying pharmacogenetics data and knowledge
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Concept representation
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Genes
Drugs
Diseases
Relational DB, frame KB
Unique identifiers, synonyms, hierarchies, concept links
Future work
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Other controlled terms
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Experimental methods, race and ethnicity, phenotype
Tools to support management of evolving terminologies
Thank you.
[email protected]
Acknowledgements:
The Pharmacogenetics Research
Network and Knowledge Base is financially supported by
grants from NIGMS, NHLBI, NHGRI, NIEHS, NCI, and
NLM within the National Institutes of Health (NIH).
Use in PharmGKB Applications
Term Selection
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Term selection (for data input or data retrieval)
1.
Pick list
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2.
Navigate hierarchy
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3.
List
Sublist
Tree
Subtree
String matching of user input
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Exact match
Ranked partial matches
Use in PharmGKB Applications
Global Search
OBJECTS
Gene
OBJECT ID
CLOB
1001
1002
Drug
1003
1004
Disease
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1005
For data retrieval
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User enters term or phrase, system finds every text occurrence
(in CLOBs)
System retrieves object IDs of gene, drug, and disease objects
that link directly or indirectly to the relevant text
Acknowledgements
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The Pharmacogenetics Research Network and
Knowledge Base is financially supported by
grants from NIGMS, NHLBI, NHGRI, NIEHS,
NCI, and NLM within the National Institutes of
Health (NIH). PharmGKB is managed at
Stanford University. This work is supported by
the NIH/NIGMS Pharmacogenetics Research
Network and Database (U01GM61374).