Pharmacogenetics and Pharmacogenomics Eric Jorgenson 2/24/9.
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Transcript of Pharmacogenetics and Pharmacogenomics Eric Jorgenson 2/24/9.
Pharmacogenetics and Pharmacogenetics and PharmacogenomicsPharmacogenomics
Eric JorgensonEric Jorgenson
2/24/92/24/9
OutlineOutline
IntroductionIntroduction
ExamplesExamples PharmacogeneticsPharmacogenetics PharmacogenomicsPharmacogenomics Environment and Drug ResponseEnvironment and Drug Response
Additional ResourcesAdditional Resources
What is Pharmacogenetics?What is Pharmacogenetics?
The study of the role of inheritance in the The study of the role of inheritance in the individual variation in drug response.individual variation in drug response.
How it differs from disease geneticsHow it differs from disease genetics Gene-environment interactionGene-environment interaction Can involve multiple gene-environment Can involve multiple gene-environment
interactionsinteractions Ethical/Methodological constraintsEthical/Methodological constraints
Events in PharmacogeneticsEvents in Pharmacogenetics
Meyer Nature Reviews Genetics 2004
PTC and PharmacogeneticsPTC and Pharmacogenetics
Meyer Nature Reviews Genetics 2004
Bimodal Distribution of PTCBimodal Distribution of PTCPTC Distribution
0
5
10
15
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45
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Raw PTC Score
Num
ber
of Subje
cts
Non-Responders
RespondersNo Toxicity Toxicity
Diplotype and PTC ScoreDiplotype and PTC Score
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2
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1 2 3 4 5 6 7 8 9 10 11 12 13 14
Raw PTC Score
Nu
mb
er o
f S
ub
ject
s
PAV/PAV
PAV/AVI
AAV/AVI
AVI/AVI
Kim et al. Science 2003
TAS2R38 Haplotype function in vitro
0
0.2
0.4
0.6
0.8
1
1.2
0.1 1 10 100 1000
PTC concentration (mM)
Rat
io P
TC
/ S
ST
PAV
PAI
PVV
PVI
AAV
AAI
AVV
AVI
Adapted from Bufe et al. Current Biology 2005
Pharmacogenetic Study Pharmacogenetic Study DesignDesign
Family StudiesFamily Studies
Linkage AnalysisLinkage Analysis
Family and Linkage are difficult to do for Family and Linkage are difficult to do for some phenotypes:some phenotypes: Severe toxicitySevere toxicity Rare diseases (need multiple affected family Rare diseases (need multiple affected family
members)members)
Pharmacogenetic Study Pharmacogenetic Study Design:Design:
Candidate Gene StudiesCandidate Gene Studies Phenotype-to-GenotypePhenotype-to-Genotype
Identify a drug response phenotypeIdentify a drug response phenotype Choose a candidate geneChoose a candidate gene
Genotype-to-PhenotypeGenotype-to-Phenotype Identify genetic polymorphisms in a gene of Identify genetic polymorphisms in a gene of
interestinterest Choose study subjects with different genotypesChoose study subjects with different genotypes Give probe drug to subjectsGive probe drug to subjects Smaller sample size neededSmaller sample size needed Best for measuring pharmacokinetic responseBest for measuring pharmacokinetic response
Drug transport, targeting, and Drug transport, targeting, and metabolismmetabolism
PharmacodynamicsPharmacodynamics
What a drug does to the bodyWhat a drug does to the body
Usually refers to the interaction of Usually refers to the interaction of the drug with the drug targetthe drug with the drug target
Pharmacogentics: Polymorphisms in Pharmacogentics: Polymorphisms in the drug targetthe drug target
PharmacokineticsPharmacokinetics How a drug is processed by the bodyHow a drug is processed by the body ADMEADME
AbsorptionAbsorption DistributionDistribution MetabolismMetabolism ExcretionExcretion
Drug LevelsDrug Levels EfficacyEfficacy ToxicityToxicity
Drug levels in the bodyDrug levels in the body
Plasma concentrationPlasma concentration Therapeutic windowTherapeutic window
Metabolic RatioMetabolic Ratio Compare blood vs. urineCompare blood vs. urine Probe drugProbe drug Can be measured over timeCan be measured over time
OutlineOutline
IntroductionIntroduction
ExamplesExamples PharmacogeneticsPharmacogenetics PharmacogenomicsPharmacogenomics Environment and Drug ResponseEnvironment and Drug Response
Additional ResourcesAdditional Resources
Phillips et al. JAMA 2001
Thiopurine S-methyltransferase Thiopurine S-methyltransferase (TPMT)(TPMT)
Drugs:Drugs: 6-mercaptopurine6-mercaptopurine azathiopurineazathiopurine
Diseases:Diseases: Acute lymphoblastic leukemiaAcute lymphoblastic leukemia Inflammatory bowel diseaseInflammatory bowel disease
Toxicity:Toxicity: Fatal myelosuppressionFatal myelosuppression Hematopoietic toxicityHematopoietic toxicity
TPMT and 6-mercaptopurineTPMT and 6-mercaptopurine
Pharmacogenetics of TPMTPharmacogenetics of TPMT
TPMT Haplotypes and TPMT Haplotypes and ActivityActivity
Standard TPMT DosingStandard TPMT Dosing
Drug Exposure and ToxicityDrug Exposure and Toxicity
Genotype Specific TPMT Genotype Specific TPMT DosingDosing
Drug Exposure and ToxicityDrug Exposure and Toxicity
Pharmacogenetics of Pharmacogenetics of AcetylationAcetylation
Weinshilboum NEJM 2003
NAT2 and Race/EthnicityNAT2 and Race/Ethnicity
Pharmacogenetics of Pharmacogenetics of CYP2D6CYP2D6
Weinshilboum NEJM 2003
CYP2D6 Copy Number Polymorphism CYP2D6 Copy Number Polymorphism and Nortriptyline Metabolic Ratioand Nortriptyline Metabolic Ratio
Meyer Nature Reviews Genetics 2004
Plasma Concentration of Nortriptyline Plasma Concentration of Nortriptyline vs. CYP2D6 Copy Numbervs. CYP2D6 Copy Number
Weinshilboum NEJM 2003
CYP2D6 and Race/EthnicityCYP2D6 and Race/Ethnicity
Pharmacogenetics and Pharmacogenetics and Race/EthnicityRace/Ethnicity
Weinshilboum NEJM 2003
Drug Metabolism and ADRsDrug Metabolism and ADRs
OutlineOutline
IntroductionIntroduction
ExamplesExamples PharmacogeneticsPharmacogenetics PharmacogenomicsPharmacogenomics Environment and Drug ResponseEnvironment and Drug Response
Additional ResourcesAdditional Resources
Pharmacogenetics and Pharmacogenetics and PharmacogenomicsPharmacogenomics
What is PharmacoWhat is Pharmacogenomicsgenomics and how is it different from and how is it different from
PharmacoPharmacogeneticsgenetics?? Genomic scaleGenomic scale
Array based platformsArray based platforms
DNA: genetic variationDNA: genetic variation RNA: gene expressionRNA: gene expression Protein: protein activity Protein: protein activity
PharmacogenomicsPharmacogenomics
Evans and Relling Nature 2004
Genome-wide Association Genome-wide Association and Drug Responseand Drug Response
GWAS Catalog: GWAS Catalog: http://www.genome.gov/26525384
Nicotine DependenceNicotine Dependence Long QT SyndromeLong QT Syndrome Statin-induced MyopathyStatin-induced Myopathy
Study of the Effectiveness of Additional Study of the Effectiveness of Additional Reductions in Cholesterol and Reductions in Cholesterol and
Homocysteine (SEARCH)Homocysteine (SEARCH)
Randomized TrialRandomized Trial 12,064 participants12,064 participants Prior MIPrior MI Simvastatin: 80mg vs. 20mgSimvastatin: 80mg vs. 20mg
6,031 on 80mg6,031 on 80mg 49 definite myopathy cases49 definite myopathy cases 49 incipient myopathy cases49 incipient myopathy cases
SEARCH Consortium NEJM 2008
Selection of subjects for Selection of subjects for genotypinggenotyping
96 cases on 80mg simvastatin96 cases on 80mg simvastatin 48 definite myopathy48 definite myopathy 48 incipient myopathy48 incipient myopathy
96 matched controls on 80mg simvastatin96 matched controls on 80mg simvastatin SexSex AgeAge eGFReGFR Amiodarone useAmiodarone use
SEARCH Consortium NEJM 2008
Subjects and Genotyping Subjects and Genotyping platformplatform
85 cases, 90 controls85 cases, 90 controls 1 case dropped for non-European 1 case dropped for non-European
ancestryancestry Others dropped for lack of DNAOthers dropped for lack of DNA
Illumina HumanHap300Illumina HumanHap300 318,237 SNPs318,237 SNPs 316,184 SNPs passed QC316,184 SNPs passed QC
SEARCH Consortium NEJM 2008
Manhattan Plot of GWASManhattan Plot of GWAS
SEARCH Consortium NEJM 2008
Replication (?)Replication (?) Heart Protection StudyHeart Protection Study 40mg simvastatin vs. placebo40mg simvastatin vs. placebo
40mg: 23 myopathy cases40mg: 23 myopathy cases Placebo: 9 myopathy casesPlacebo: 9 myopathy cases
16,664 genotyped participants16,664 genotyped participants 21 cases21 cases 16,643 controls16,643 controls Relative Risk = 2.6 per alleleRelative Risk = 2.6 per allele Compared to Odds Ratio = 4.4 per alleleCompared to Odds Ratio = 4.4 per allele
SEARCH Consortium NEJM 2008
Myopathy attributable to rs4149056 within patients on 80mg
of Simvastatin
SEARCH Consortium NEJM 2008
Gene Expression Diagnostic Gene Expression Diagnostic TestTest
Oncotype DX
Tests expression of 21 genes in Tests expression of 21 genes in tumor samplestumor samples
Recurrence Score of 0-100Recurrence Score of 0-100 Women with higher scores are more Women with higher scores are more
likely to benefit from chemotherapylikely to benefit from chemotherapy
OutlineOutline
IntroductionIntroduction
ExamplesExamples PharmacogeneticsPharmacogenetics PharmacogenomicsPharmacogenomics Environment and Drug ResponseEnvironment and Drug Response
Additional ResourcesAdditional Resources
PharmacoenvironmentPharmacoenvironment
Grapefruit juice-felodipine interactionGrapefruit juice-felodipine interaction
bergamottin inhibition of CYP3A4 in bergamottin inhibition of CYP3A4 in the small intestinethe small intestine
Drug levelsDrug levels
Dahan and Altman EJCN 2004
Grapefruit juice drug Grapefruit juice drug interactionsinteractions
Dahan and Altman EJCN 2004
OutlineOutline
IntroductionIntroduction
ExamplesExamples PharmacogeneticsPharmacogenetics PharmacogenomicsPharmacogenomics Environment and Drug ResponseEnvironment and Drug Response
Additional ResourcesAdditional Resources
Reviews of Reviews of PharmacogeneticsPharmacogenetics
Evans and Mcleod NEJM 2003Evans and Mcleod NEJM 2003 Goldstein, Tate, Sisodiya Nature Goldstein, Tate, Sisodiya Nature
Reviews Genetics 2003Reviews Genetics 2003 Meyer Nature Reviews Genetics 2004Meyer Nature Reviews Genetics 2004 Evans and Relling Nature 2004Evans and Relling Nature 2004 Wilkinson NEJM 2005Wilkinson NEJM 2005
More on PharmacogeneticsMore on Pharmacogenetics
Pharmacogenetics Knowledge Base (Pharmacogenetics Knowledge Base (PharmGKB) )
http://www.PharmGKb.orghttp://www.PharmGKb.org
More ExamplesMore Examples
Evans and Mcleod NEJM 2003Evans and Mcleod NEJM 2003
Even more ExamplesEven more Examples
Evans and Mcleod NEJM Evans and Mcleod NEJM 20032003