Genes, Drugs, and Diseases for a
Pharmacogenetics Knowledge Base
Diane E. Oliver, MD, PhDStanford University
SOFG – Nov. 19, 2002
Outline
Pharmacogenetics and PharmGKB Sources of genes, drugs, and
diseases Representation of concepts Maintenance Summary
Outline
Pharmacogenetics and PharmGKB Sources of genes, drugs, and
diseases Representation of concepts Maintenance Summary
Pharmacogenetics
Pharmacogenetics = the science of how genes influence an individual’s response to drugs
Gene–drug associationGene Drug Respon
se
Adverse Effect
Efficacy( )
Adverse Effect 6-mercaptopurine + TPMT
Fatal bone marrow suppression
Pre-prescription genetic testing
Efficacy Codeine + CYP2D6
7-10% of Caucasians poor metabolizers
No effect on pain
Research in Pharmacogenetics
Receptors
Enzymes Transporters
Ion Channels
Tamoxifen
CYP2D6, CYP2C19, CYP3A5 SLC6A4 (SERT)
Paroxetine
NR3C1 (GR) SCN5A, KCNH2
Flunisolide Quinidine
?Adverse Effects:Hot flashes, cholesterol, clotting
Efficacy (Depression):Responders ornonresponders
Efficacy (Asthma):Responders ornonresponders
Adverse Effects:Torsades depointes, long QT syndrome
Research in Pharmacogenetics
Receptors
Enzymes Transporters
Ion Channels
Tamoxifen
CYP2D6, CYP2C19, CYP3A5 SLC6A4 (SERT)
Paroxetine
NR3C1 (GR) SCN5A, KCNH2
Flunisolide Quinidine
?Adverse Effects:Hot flashes, cholesterol, clotting factors
Efficacy (Depression):Responders ornonresponders
Efficacy (Asthma):Responders ornonresponders
Adverse Effects:Torsades depointes, long QT syndrome
Research in Pharmacogenetics
Receptors
Enzymes Transporters
Ion Channels
Tamoxifen
CYP2D6, CYP2C19, CYP3A5 SLC6A4 (SERT)
Paroxetine
NR3C1 (GR) SCN5A, KCNH2
Flunisolide Quinidine
?Adverse Effects:Hot flashes, cholesterol, clotting factors
Efficacy (Depression):Responders ornonresponders
Efficacy (Asthma):Responders ornonresponders
Adverse Effects:Torsades depointes, long QT syndrome
Research in Pharmacogenetics
Receptors
Enzymes Transporters
Ion Channels
Tamoxifen
CYP2D6, CYP2C19, CYP3A5 SLC6A4 (SERT)
Paroxetine
NR3C1 (GR) SCN5A, KCNH2
FlunisolideQuinidine
?Adverse Effects:Hot flashes, cholesterol, clotting factors
Efficacy (Depression):Responders ornonresponders
Efficacy (Asthma):Responders ornonresponders
Adverse Effects:Torsades depointes, long QT syndrome
Research in Pharmacogenetics
Receptors
Enzymes Transporters
Ion Channels
Tamoxifen
CYP2D6, CYP2C19, CYP3A5 SLC6A4 (SERT)
Paroxetine
NR3C1 (GR) SCN5A, KCNH2
Flunisolide Quinidine
?Adverse Effects:Hot flashes, cholesterol, clotting factors
Efficacy (Depression):Responders ornonresponders
Efficacy (Asthma):Responders ornonresponders
Adverse Effects:Torsades depointes, long QT syndrome
PharmGKB What is PharmGKB?
A project A web site http://pharmgkb.org A knowledge base A team
Goals of PharmGKB (the project) 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
Pharmacogenetics and PharmGKB Sources of genes, drugs, and
diseases Representation of concepts Maintenance Summary
Sources of Genes, Drugs, and Diseases
Goals Leverage off the work of others Coordinate with national and international
communities Maintainable Locally extensible
Concept Type Sources
Genes HGNC, LocusLink
Drugs NDF-RT, Orange Book
Diseases MeSH
Sources of Concepts
HGNC LocusLink NDF-RT Orange Book MeSH
PharmGKB
Gene, Drug, DiseaseTerminologies
Gene Source - HGNC
Approved Gene Name ATP-binding cassette, sub-family B (MDR/TAP), member 1
Approved Gene Symbol
ABCB1
Previous Symbol PGY1, MDR1Aliases P-gpPrevious Gene Name
LocusLink ID 5243
HUGO Gene Nomenclature Committee
http://www.gene.ucl.ac.uk/public-files/nomen/searchdata.txt
Gene Source - LocusLinkLocusLinkID 5243Alternate symbols MDR1, P-gp, PGY1, ABC20, GP170 Aliases multidrug resistance 1 Cytogenetic location
7q21.1
OMIM phenotype Colchicine resistanceGene 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
<conceptDef><name>ASPIRIN 325MG TAB [NDC: 00839676409]</name><namespace>NDF</namespace><primitive/><kind>DRUG_KIND</kind><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>
<name>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 – NDF-RT
Drug Source – Orange Book
PROCAINAMIDE HYDROCHLORIDE~Capsule; Oral~PRONESTYL~APOTHECON~250MG~007335~001~AB~Approved prior to Jan 1, 1982~No~RXDICYCLOMINE HYDROCHLORIDE~Capsule; Oral~BENTYL~AVENTIS PHARMS~10MG~007409~003~AB~OCT 15, 1984~Yes~RXNOREPINEPHRINE BITARTRATE~Injectable; Injection~LEVOPHED~ABBOTT~EQ 1MG BASE/ML~007513~001~~Approved prior to Jan 1, 1982~Yes~RXMETHIMAZOLE~Tablet; Oral~TAPAZOLE~LILLY~5MG~007517~002~AB~Approved prior to Jan 1, 1982~No~RXASPIRIN~Tablet, Extended Release; Oral~8-HOUR BAYER ~BAYER~650MG~016030~001~~Approved prior to Jan 1, 1982~No~DISCNHYDROCORTISONE~Tablet; Oral~CORTEF~PHARMACIA AND UPJOHN~10MG~008697~001~BP~ApproWARFARIN 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*NEWRECORDRECTYPE = DMH = AsthmaAQ = BL CF CI CL CN CO DH DI DT EC EH EM EN EP ET GE HI IM ME MI MO NUPA PC PP PS PX RA RH RI RT SU TH UR US VE VIPRINT ENTRY = Asthma, Bronchial|T047|NON|EQV|UNK (19XX)|840210|abcdefPRINT ENTRY = Bronchial Asthma|T047|NON|EQV|UNK (19XX)|840210|abcdefENTRY = AsthmasENTRY = Asthmas, BronchialENTRY = Bronchial AsthmasMN = C08.127.108MN = C08.381.495.108MN = C08.674.095MN = C20.543.480.680.095FX = Anti-Asthmatic AgentsMH_TH = NLM (1966)MS = A form of bronchial disorder associated with airway obstruction,marked by recurrent attacks of paroxysmal dyspnea, with wheezing due tospasmodic contraction of the bronchi.
Outline
Pharmacogenetics and PharmGKB Sources of genes, drugs, and
diseases Representation of concepts Maintenance Summary
Representation of Concepts
Two approaches KB = Knowledge base DB = Relational database
KB implementation http://protege.stanford.edu Protégé: Frame-based knowledge representation
system Frames and slots – hierarchies, links among
concepts DB implementation
Oracle: Relational database management system Tables and columns – indexed lookups, joins
Representation of Concepts
Relational DB Genes Gene Symbols Gene Synonyms Gene OMIM Phenotypes Gene Products Gene Golden Path
Sequence Drugs Drug Synonyms Diseases Disease Synonyms
Table Names GeneID
DrugID
DiseaseID
Outline
Pharmacogenetics and PharmGKB Sources of genes, drugs, and
diseases Representation of concepts Maintenance Summary
Maintenance of PharmGKB Data
HGNC LocusLink VA-NDF Orange Book MeSH
PharmGKBPharmGKB
Archive
Gene, Drug, DiseaseTerminologies ValidFrom
ValidTo
01-01-2000
ValidFrom ValidTo
01-01-2000
03-04-2002
Maintenance of Concepts
HGNC LocusLink VA-NDF Orange Book MeSH
PharmGKBPharmGKB
Archive
Gene, Drug, DiseaseTerminologies
local additions
Outline
Pharmacogenetics and PharmGKB Sources of genes, drugs, and
diseases Representation of concepts Maintenance Summary
Summary Controlled terminologies essential for indexing and
querying pharmacogenetics data and knowledge Genes Drugs Diseases
Concept representation Relational DB, frame KB Unique identifiers, synonyms, hierarchies, concept links
Future work Other controlled terms
Experimental methods, race and ethnicity, phenotype Tools to support management of evolving terminologies
Thank you.
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 Term selection (for data input or
data retrieval)1. Pick list
List Sublist
2. Navigate hierarchy Tree Subtree
3. String matching of user input Exact match Ranked partial matches
Use in PharmGKB Applications
Global Search
For data retrieval 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
1001
1002
1003
1004
1005
Gene
Disease
Drug
OBJECT ID CLOBOBJECTS
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). PharmGKB is managed at Stanford University. This work is supported by the NIH/NIGMS Pharmacogenetics Research Network and Database (U01GM61374).
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