Interactions Eric Jorgenson EPI 217 2/22/11. Outline Gene-Environment Interaction Gene-Gene...
-
Upload
christopher-stevens -
Category
Documents
-
view
218 -
download
0
Transcript of Interactions Eric Jorgenson EPI 217 2/22/11. Outline Gene-Environment Interaction Gene-Gene...
Interactions
Eric JorgensonEPI 2172/22/11
Outline
• Gene-Environment Interaction
• Gene-Gene Interaction
• Pharmacogenetics
• Pharmacogenomics
• Mental retardation and seizures• 1/15,000 live births
o 1/100,000 in Finlando 1/2,600 in Turkey
PKU: Phenylketonuria
Phenylalanine Metabolism
PKU: Phenylketonuria Causes
• Mutations in Phenylalanine Hydroxylase (PAH)
• Dietary Phenylalanine
• Both are necessary• Neither is sufficient
PKU: Gene-Environment Interaction
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
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
Multiplicative Effects
G+E+ 45 15G+E- 15 5G-E+ 9 3G-E- 3 1
Strata RiskAbsolute
Ratio Odds
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
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
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
Outline
• Gene-Environment Interaction
• Gene-Gene Interaction
• Pharmacogenetics
• Pharmacogenomics
Gene-Gene Interaction Models
Marchini et al. Nature Genetics 2005
GWAS of Psoriasis
Strange et al. Nature Genetics 2010
Gene-Gene Interaction
Strange et al. Nature Genetics 2010
Outline
• Gene-Environment Interaction
• Gene-Gene Interaction
• Pharmacogenetics
• Pharmacogenomics
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
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
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:o Severe toxicityo Rare diseases (need multiple affected family
members)
Pharmacodynamics
• How a drug acts
• Drug target
Pharmacokinetics
• How a drug is processed• ADME
o Absorptiono Distributiono Metabolismo Excretion
• Drug Levels (dosage)o Efficacyo Toxicity
Drug levels in the body
• Plasma concentration
• Metabolic Ratioo Compare blood vs. urineo Probe drugo Can be measured over time
TPMT and 6-mercaptopurine
Thiopurine S-methyltransferase (TPMT)
• Drugs:o 6-mercaptopurineo azathiopurine
• Diseases:o Acute lymphoblastic leukemiao Inflammatory bowel disease
• Toxicity:o Fatal myelosuppressiono 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
Meyer Nature Reviews Genetics 2004
CYP2D6 Copy Number Variation
Pharmacogenetics of Nortriptyline
Weinshilboum NEJM 2003
CYP2D6 and Race/Ethnicity
Pharmacogenetics and Race/Ethnicity
Weinshilboum NEJM 2003
Drug Metabolism and ADRs
Outline
• Gene-Environment Interaction
• Gene-Gene Interaction
• Pharmacogenetics
• Pharmacogenomics
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?