Pharmacogenomics

Eric Jorgenson

Outline

• Introduction

• Pharmacogenetics– TPMT– CYP2D6

• Pharmacogenomics– GWAS– Gene Expression

What is Pharmacogenetics?

• The study of the role of inheritance in the individual variation in drug response.

• Efficacy

• Toxicity

Phillips et al. JAMA 2001

Adverse Drug Reactions are common

Events in Pharmacogenetics

Meyer Nature Reviews Genetics 2004

PTC and Pharmacogenetics

Meyer Nature Reviews Genetics 2004

Bimodal Distribution of PTC

PTC 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

Number of Subjects

Non-Responders

RespondersNo Toxicity Toxicity

Diplotype 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

Number of Subjects

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 ( μM)

/ Ratio PTC SST

PAV

PAI

PVV

PVI

AAV

AAI

AVV

AVI

Adapted from Bufe et al. Current Biology 2005

Pharmacogenetic Study Design

• Family Studies

• Linkage Analysis

• Candidate Gene Studies

• Family and Linkage are difficult to do for some phenotypes:– Severe toxicity– Rare diseases (need multiple affected family

members)

Drug transport, targeting, and metabolism

Pharmacodynamics

• How a drug acts

• Drug target

Pharmacokinetics

• How a drug is processed• ADME

– Absorption– Distribution– Metabolism– Excretion

• Drug Levels (dosage)– Efficacy– Toxicity

Drug levels in the body

• Plasma concentration

• Metabolic Ratio– Compare blood vs. urine– Probe drug– Can be measured over time

Outline

• Introduction

• Pharmacogenetics– TPMT– CYP2D6

• Pharmacogenomics– GWAS– Gene Expression

TPMT and 6-mercaptopurine

Thiopurine S-methyltransferase (TPMT)

• Drugs:– 6-mercaptopurine– azathiopurine

• Diseases:– Acute lymphoblastic leukemia– Inflammatory bowel disease

• Toxicity:– Fatal myelosuppression– Hematopoietic toxicity

Pharmacogenetics of TPMT

TPMT Haplotypes and Activity

Standard TPMT Dosing

Drug Exposure and Toxicity

Genotype Specific TPMT Dosing

Drug Exposure and Toxicity

More on TPMT

• Pharmacogenetics Knowledge Base (PharmGKB)

• http://www.PharmGKb.org

Pharmacogenetics of CYP2D6

Weinshilboum NEJM 2003

Meyer Nature Reviews Genetics 2004

CYP2D6 Copy Number Variation

Pharmacogenetics of Nortriptyline

Weinshilboum NEJM 2003

CYP2D6 and Race/Ethnicity

Pharmacogenetics and Race/Ethnicity

Weinshilboum NEJM 2003

Drug Metabolism and ADRs

GenotypePhenotype Studies

• Survey genetic variation in genes of interest

• Test genetic variants in laboratory studies

• Recruit subjects with known variant genotypes

• Pharmacogenomics of Membrane Transporters (PMT)

Outline

• Introduction

• Pharmacogenetics– TPMT– CYP2D6

• Pharmacogenomics– GWAS– Gene Expression

Pharmacogenetics and Pharmacogenomics

What is Pharmacogenomics and how is it different from Pharmacogenetics?

• Genomic scale

• Array based platforms

Pharmacogenomics

Evans and Relling Nature 2004

GWAS of Statin-Induced MyopathyGWAS of Statin-Induced Myopathy

Quantile-Quantile (QQ) PlotQuantile-Quantile (QQ) Plot

Manhattan PlotManhattan Plot

Odds ratios for rs4149056

Cumulative risk of myopathy

GWAS of Platelet Aggregation in

Response to Clopidogrel

QuickTime™ and a decompressor

are needed to see this picture.

Platelet Aggregation inResponse to Clopidogrel

Shuldiner et al. JAMA 2009

Dubai Plot

CYP2C19*2 modifies platelet aggregation in response to clopidogrel

Event-free survival

3 GWAS of sustained virological response to PEGylated interferon- and ribavirin

QuickTime™ and a decompressor

are needed to see this picture.

QuickTime™ and a decompressor

are needed to see this picture.

QuickTime™ and a decompressor

are needed to see this picture.

Manhattan Plot

Tanaka et al. Nature Genetics 2009

Variation in Il28B predicts Sustained Virological Response in Hepatitis C

Ge Nature Genetics 2009

Haplotype effects

Supiah et al. Nature Genetics 2009

GWAS of acenocoumarol mainenance dosage

QuickTime™ and a decompressor

are needed to see this picture.

Acenocoumarol maintenance dosage

Teichert et al. Human Molecular Genetics 2009

Acenocoumarol maintenance dosage adjusted for top SNPs

Acenocumarol dosage variance explained

ROC Curves

Attia et al. JAMA 2009

Challenges for Pharmacogenomics

• How predictive is a test?

• Does the test apply to all groups?

• Is a test superior to current clinical practice?

• Will testing improve outcomes?

• Is testing cost effective?

Oncotype uses 21 genes to calculate a recurrence score

PROLIFERATIONKi-67STK15SurvivinCyclin B1MYBL2

ESTROGENERPRBcl2SCUBE2

INVASIONStromelysin 3Cathepsin L2

HER2GRB7HER2

BAG1GSTM1

REFERENCEBeta-actinGAPDHRPLPOGUSTFRC

CD68

16 Cancer and 5 Reference Genes From 3 Studies

Paik et al. N Engl J Med. 2004;351: 2817-2826

Oncotype Recurrence Score

0%

5%

10%

15%

20%

25%

30%

35%

40%

0 5 10 15 20 25 30 35 40 45 50

Recurrence Score

Distant Recurrence at 10 Years

Low-Risk Group High-Risk Group Intermediate- Risk Group

95% CI

RS is 30. What is the chance of recurrence within 10 years?

RS is 30. What is the chance of recurrence within 10 years?

Paik et al. N Engl J Med. 2004;351:2817-2826

Recurrence Score and 10-Year Distant Recurrence-Free Survival

Summary of Treatment Benefit Related to RS and Breast Cancer Death in NSABP B-14 and B-20

Largest Tamoxifen Benefit Observed in Low- and Intermediate-Risk Recurrence Score Groups

TAMOXIFEN BENEFIT

Largest Chemotherapy Benefit Observed in High-Risk Recurrence Score Group

CHEMOTHERAPYBENEFIT

Chemotherapy benefit in high RS patients

Paik et al. J Clin Oncol. 2006;24:3726-3734

28% Absolute Benefit

Little, if any, benefit

All patients

Low RS

High RS

Intermediate RS