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Interactions
Eric JorgensonEPI 2172/22/11
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Outline
• Gene-Environment Interaction
• Gene-Gene Interaction
• Pharmacogenetics
• Pharmacogenomics
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• Mental retardation and seizures• 1/15,000 live births
o 1/100,000 in Finlando 1/2,600 in Turkey
PKU: Phenylketonuria
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Phenylalanine Metabolism
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PKU: Phenylketonuria Causes
• Mutations in Phenylalanine Hydroxylase (PAH)
• Dietary Phenylalanine
• Both are necessary• Neither is sufficient
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PKU: Gene-Environment Interaction
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Strata Cases Controls
Gene (G+)Environment (E+)
a b
Gene (G+)No Environment (E-)
c d
No Gene (G-) Environment (E+)
e f
No Gene (G-) No Environment (E-)
g h
Gene-Environment Interaction
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Gene-Environment Interaction
Strata Cases Controls
G+E+ a b
G+E- c d
G-E+ e f
G-E- g h
Odds Ratio (OR)
ah / bg
ch / dg
eh / fg
1
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Multiplicative Effects
G+E+ 45 15G+E- 15 5G-E+ 9 3G-E- 3 1
Strata RiskAbsolute
Ratio Odds
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Multiplicative Effects
OR Interaction = ORG+E+ / ORG+E- ORG-E+
If OR Interaction = 1, multiplicative effects
Example: OR Interaction = 15 / 5 x 3OR Interaction = 1
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Factor V Leiden Mutations, Oral Contraceptive Use, and Venous Thrombosis
Strata Cases Controls
G+E+ 25 2
G+E- 10 4
G-E+ 84 63
G-E- 36 100
OR
34.7
6.9
3.7
Reference
Total 155 169Vanderbroucke et al. The Lancet 1994
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Evidence for G-E Interaction
OR Interaction =
34.7 / 6.9 x 3.7 = 1.4
Strata OR
G+E+ 34.7
G+E- 6.9
G-E+ 3.7
G-E- Ref
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Outline
• Gene-Environment Interaction
• Gene-Gene Interaction
• Pharmacogenetics
• Pharmacogenomics
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Gene-Gene Interaction Models
Marchini et al. Nature Genetics 2005
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GWAS of Psoriasis
Strange et al. Nature Genetics 2010
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Gene-Gene Interaction
Strange et al. Nature Genetics 2010
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Outline
• Gene-Environment Interaction
• Gene-Gene Interaction
• Pharmacogenetics
• Pharmacogenomics
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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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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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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:o Severe toxicityo Rare diseases (need multiple affected family
members)
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Pharmacodynamics
• How a drug acts
• Drug target
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Pharmacokinetics
• How a drug is processed• ADME
o Absorptiono Distributiono Metabolismo Excretion
• Drug Levels (dosage)o Efficacyo Toxicity
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Drug levels in the body
• Plasma concentration
• Metabolic Ratioo Compare blood vs. urineo Probe drugo Can be measured over time
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TPMT and 6-mercaptopurine
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Thiopurine S-methyltransferase (TPMT)
• Drugs:o 6-mercaptopurineo azathiopurine
• Diseases:o Acute lymphoblastic leukemiao Inflammatory bowel disease
• Toxicity:o Fatal myelosuppressiono 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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Meyer Nature Reviews Genetics 2004
CYP2D6 Copy Number Variation
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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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Outline
• Gene-Environment Interaction
• Gene-Gene Interaction
• Pharmacogenetics
• Pharmacogenomics
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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 Myopathy
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Quantile-Quantile (QQ) Plot
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Manhattan 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 inResponse 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?