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


Bimodal Distribution of PTCBimodal Distribution of PTCPTC Distribution

0

5

10

15

20

25

30

35

40

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

0

2

4

6

8

10

12

14

16

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




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


CYP2D6 Copy Number Polymorphism CYP2D6 Copy Number Polymorphism and Nortriptyline Metabolic Ratioand Nortriptyline Metabolic Ratio


Plasma Concentration of Nortriptyline Plasma Concentration of Nortriptyline vs. CYP2D6 Copy Numbervs. CYP2D6 Copy Number


CYP2D6 and Race/EthnicityCYP2D6 and Race/Ethnicity

Pharmacogenetics and Pharmacogenetics and Race/EthnicityRace/Ethnicity


Drug Metabolism and ADRsDrug Metabolism and ADRs

OutlineOutline




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

http://www.genome.gov/26525384

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


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


Manhattan Plot of GWASManhattan Plot of GWAS


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


Myopathy attributable to rs4149056 within patients on 80mg

of Simvastatin


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

http://www.oncotypedx.com/HealthcareProfessional/ClinicalSummary.aspx?Sid=4

OutlineOutline




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




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

http://www.pharmgkb.org/search/annotatedGene/tpmt/

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

Date post:	01-Jan-2016
Category:	Documents
Upload:	sharlene-caldwell
View:	229 times
Download:	1 times

Pharmacogenetics and Pharmacogenomics Eric Jorgenson 2/24/9.

Documents