Pharmacogenomics
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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

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


Adverse Drug Reactions are common

Phillips et al. JAMA 2001


Events in Pharmacogenetics

Meyer Nature Reviews Genetics 2004


PTC and Pharmacogenetics

Meyer Nature Reviews Genetics 2004


Bimodal Distribution of PTC

Non-Responders

No Toxicity

Responders

Toxicity


Diplotype and PTC Score

Kim et al. Science 2003


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


CYP2D6 Copy Number Variation

Meyer Nature Reviews Genetics 2004


Pharmacogenetics of Nortriptyline

Weinshilboum NEJM 2003


CYP2D6 and Race/Ethnicity


Pharmacogenetics and Race/Ethnicity

Weinshilboum NEJM 2003


Drug Metabolism and ADRs


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)


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 Myopathy


Quantile-Quantile (QQ) Plot


Manhattan Plot


Odds ratios for rs4149056


Cumulative risk of myopathy


GWAS of Platelet Aggregation inResponse to Clopidogrel


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


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


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?


PROLIFERATION

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

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

95% CI


Recurrence Score 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


TAMOXIFEN

BENEFIT

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


CHEMOTHERAPY

BENEFIT

Largest Chemotherapy Benefit Observed in High-Risk Recurrence Score Group


Little, if any, benefit

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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