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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

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

manhattan plot1
Manhattan Plot

Tanaka et al. Nature Genetics 2009

haplotype effects
Haplotype effects

Supiah et al. Nature Genetics 2009

acenocoumarol maintenance dosage
Acenocoumarol maintenance dosage

Teichert et al. Human Molecular Genetics 2009

roc curves
ROC Curves

Attia et al. JAMA 2009

challenges for pharmacogenomics
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
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
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
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
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 Tamoxifen Benefit Observed in Low- and Intermediate-Risk Recurrence Score Groups
chemotherapy benefit in high rs patients
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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