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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
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
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