pharmacogenomics eric jorgenson. outline introduction pharmacogenetics –tpmt –cyp2d6...
TRANSCRIPT
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Pharmacogenomics
Eric Jorgenson
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Outline
• Introduction
• Pharmacogenetics– TPMT– CYP2D6
• Pharmacogenomics– GWAS– Gene Expression
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What is Pharmacogenetics?
• The study of the role of inheritance in the individual variation in drug response.
• Efficacy
• Toxicity
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Phillips et al. JAMA 2001
Adverse Drug Reactions are common
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Events in Pharmacogenetics
Meyer Nature Reviews Genetics 2004
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PTC and Pharmacogenetics
Meyer Nature Reviews Genetics 2004
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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
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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
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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
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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)
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Drug transport, targeting, and metabolism
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Pharmacodynamics
• How a drug acts
• Drug target
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Pharmacokinetics
• How a drug is processed• ADME
– Absorption– Distribution– Metabolism– Excretion
• Drug Levels (dosage)– Efficacy– Toxicity
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Drug levels in the body
• Plasma concentration
• Metabolic Ratio– Compare blood vs. urine– Probe drug– Can be measured over time
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Outline
• Introduction
• Pharmacogenetics– TPMT– CYP2D6
• Pharmacogenomics– GWAS– Gene Expression
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TPMT and 6-mercaptopurine
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Thiopurine S-methyltransferase (TPMT)
• Drugs:– 6-mercaptopurine– azathiopurine
• Diseases:– Acute lymphoblastic leukemia– Inflammatory bowel disease
• Toxicity:– Fatal myelosuppression– Hematopoietic toxicity
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Pharmacogenetics of TPMT
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TPMT Haplotypes and Activity
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Standard TPMT Dosing
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Drug Exposure and Toxicity
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Genotype Specific TPMT Dosing
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Drug Exposure and Toxicity
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More on TPMT
• Pharmacogenetics Knowledge Base (PharmGKB)
• http://www.PharmGKb.org
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Pharmacogenetics of CYP2D6
Weinshilboum NEJM 2003
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Pharmacogenetics of Nortriptyline
Weinshilboum NEJM 2003
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CYP2D6 and Race/Ethnicity
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Pharmacogenetics and Race/Ethnicity
Weinshilboum NEJM 2003
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Drug Metabolism and ADRs
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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)
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Outline
• Introduction
• Pharmacogenetics– TPMT– CYP2D6
• Pharmacogenomics– GWAS– Gene Expression
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Pharmacogenetics and Pharmacogenomics
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What is Pharmacogenomics and how is it different from Pharmacogenetics?
• Genomic scale
• Array based platforms
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Pharmacogenomics
Evans and Relling Nature 2004
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GWAS of Statin-Induced MyopathyGWAS of Statin-Induced Myopathy
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Quantile-Quantile (QQ) PlotQuantile-Quantile (QQ) Plot
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Manhattan PlotManhattan Plot
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Odds ratios for rs4149056
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Cumulative risk of myopathy
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GWAS of Platelet Aggregation in
Response to Clopidogrel
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Platelet Aggregation inResponse to Clopidogrel
Shuldiner et al. JAMA 2009
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Dubai Plot
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CYP2C19*2 modifies platelet aggregation in response to clopidogrel
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Event-free survival
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3 GWAS of sustained virological response to PEGylated interferon- and ribavirin
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Manhattan Plot
Tanaka et al. Nature Genetics 2009
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Variation in Il28B predicts Sustained Virological Response in Hepatitis C
Ge Nature Genetics 2009
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Haplotype effects
Supiah et al. Nature Genetics 2009
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GWAS of acenocoumarol mainenance dosage
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Acenocoumarol maintenance dosage
Teichert et al. Human Molecular Genetics 2009
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Acenocoumarol maintenance dosage adjusted for top SNPs
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Acenocumarol dosage variance explained
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ROC Curves
Attia et al. JAMA 2009
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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?
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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
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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?
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Paik et al. N Engl J Med. 2004;351:2817-2826
Recurrence Score and 10-Year Distant Recurrence-Free Survival
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Summary of Treatment Benefit Related to RS and Breast Cancer Death in NSABP B-14 and B-20
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Largest Tamoxifen Benefit Observed in Low- and Intermediate-Risk Recurrence Score Groups
TAMOXIFEN BENEFIT
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Largest Chemotherapy Benefit Observed in High-Risk Recurrence Score Group
CHEMOTHERAPYBENEFIT
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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