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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.

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Pharmacogenomics

Pharmacogenomics

Eric Jorgenson


Outline
Outline

  • Introduction

  • Pharmacogenetics

    • TPMT

    • CYP2D6

  • Pharmacogenomics

    • GWAS

    • Gene Expression


What is pharmacogenetics
What is Pharmacogenetics?

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

  • Efficacy

  • Toxicity


Adverse drug reactions are common
Adverse Drug Reactions are common

Phillips et al. JAMA 2001


Events in pharmacogenetics
Events in Pharmacogenetics

Meyer Nature Reviews Genetics 2004


Ptc and pharmacogenetics
PTC and Pharmacogenetics

Meyer Nature Reviews Genetics 2004


Bimodal distribution of ptc
Bimodal Distribution of PTC

Non-Responders

No Toxicity

Responders

Toxicity


Diplotype and ptc score
Diplotype and PTC Score

Kim et al. Science 2003



Pharmacogenetic study design
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)



Pharmacodynamics
Pharmacodynamics

  • How a drug acts

  • Drug target


Pharmacokinetics
Pharmacokinetics

  • How a drug is processed

  • ADME

    • Absorption

    • Distribution

    • Metabolism

    • Excretion

  • Drug Levels (dosage)

    • Efficacy

    • Toxicity


Drug levels in the body
Drug levels in the body

  • Plasma concentration

  • Metabolic Ratio

    • Compare blood vs. urine

    • Probe drug

    • Can be measured over time


Outline1
Outline

  • Introduction

  • Pharmacogenetics

    • TPMT

    • CYP2D6

  • Pharmacogenomics

    • GWAS

    • Gene Expression



Thiopurine s methyltransferase tpmt
Thiopurine S-methyltransferase (TPMT)

  • Drugs:

    • 6-mercaptopurine

    • azathiopurine

  • Diseases:

    • Acute lymphoblastic leukemia

    • Inflammatory bowel disease

  • Toxicity:

    • Fatal myelosuppression

    • Hematopoietic toxicity








More on tpmt
More on TPMT

  • Pharmacogenetics Knowledge Base (PharmGKB)

  • http://www.PharmGKb.org


Pharmacogenetics of cyp2d6
Pharmacogenetics of CYP2D6

Weinshilboum NEJM 2003


Cyp2d6 copy number variation
CYP2D6 Copy Number Variation

Meyer Nature Reviews Genetics 2004


Pharmacogenetics of nortriptyline
Pharmacogenetics of Nortriptyline

Weinshilboum NEJM 2003



Pharmacogenetics and race ethnicity
Pharmacogenetics and Race/Ethnicity

Weinshilboum NEJM 2003



Genotype phenotype studies
GenotypePhenotype 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)


Outline2
Outline

  • Introduction

  • Pharmacogenetics

    • TPMT

    • CYP2D6

  • Pharmacogenomics

    • GWAS

    • Gene Expression



What is pharmaco genomics and how is it different from pharmaco genetics
What is Pharmacogenomics and how is it different from Pharmacogenetics?

  • Genomic scale

  • Array based platforms


Pharmacogenomics1
Pharmacogenomics

Evans and Relling Nature 2004







Gwas of platelet aggregation in response to clopidogrel
GWAS of Platelet Aggregation inResponse to Clopidogrel


Platelet aggregation in response to clopidogrel
Platelet Aggregation inResponse to Clopidogrel

Shuldiner et al. JAMA 2009




Event free survival
Event-free survival clopidogrel



Manhattan plot1
Manhattan Plot interferon-

Tanaka et al. Nature Genetics 2009


Variation in il28b predicts sustained virological response in hepatitis c
Variation in Il28B predicts Sustained Virological Response in Hepatitis C

Ge Nature Genetics 2009


Haplotype effects
Haplotype effects in Hepatitis C

Supiah et al. Nature Genetics 2009



Acenocoumarol maintenance dosage
Acenocoumarol maintenance dosage in Hepatitis C

Teichert et al. Human Molecular Genetics 2009




Roc curves
ROC Curves in Hepatitis C

Attia et al. JAMA 2009


Challenges for pharmacogenomics
Challenges for Pharmacogenomics in Hepatitis C

  • 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

PROLIFERATION in Hepatitis C

Ki-67

STK15

Survivin

Cyclin B1

MYBL2

ESTROGEN

ER

PR

Bcl2

SCUBE2

HER2

GRB7

HER2

REFERENCE

Beta-actin

GAPDH

RPLPO

GUS

TFRC

GSTM1

BAG1

INVASION

Stromelysin 3

Cathepsin L2

CD68

Oncotype uses 21 genes to calculate a recurrence score

16 Cancer and 5 Reference Genes From 3 Studies

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


Oncotype recurrence score
Oncotype Recurrence Score in Hepatitis C

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

95% CI


Recurrence score and 10 year distant recurrence free survival
Recurrence Score in Hepatitis C and 10-Year Distant Recurrence-Free Survival

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


Summary of treatment benefit related to rs and breast cancer death in nsabp b 14 and b 20
Summary of Treatment Benefit Related to RS in Hepatitis C and Breast Cancer Death in NSABP B-14 and B-20


Largest tamoxifen benefit observed in low and intermediate risk recurrence score groups

TAMOXIFEN in Hepatitis C

BENEFIT

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


Largest chemotherapy benefit observed in high risk recurrence score group

CHEMOTHERAPY in Hepatitis C

BENEFIT

Largest Chemotherapy Benefit Observed in High-Risk Recurrence Score Group


Chemotherapy benefit in high rs patients

Little, if any, benefit in Hepatitis C

All patients

Low RS

28% Absolute Benefit

Intermediate RS

High RS

Chemotherapy benefit in high RS patients

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


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