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.

oliver@smi.stanford.edu

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).