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Georgetown
UNIVERSITY
Pharmacogenomics: Implications for
Clinical Education
Howard J Federoff, MD, PhD
Georgetown University Medical Center
Themes
» Progressive reductionism in medicine: Right
direction?
» Post-Genomics forecasting and implications of
pharmacogenomics (PGx)
» The state of PGx (Warfarin illustration)
» PGx approaches will likely be extended by systems
approaches
» Systems medicine as a paradigm
» Status of training needs for physicians of tomorrow
Progressive Reductionism: Heading in the Right
Direction?
» Galen
 Observation and reasoning; first experimental physiologist
» Mendel
 Describes ‘dominance’ and ‘recessiveness’
» Darwin
 Natural selection and key role of the environment
» Flexner
 Articulated a standard for educating physicians
» Beadle and Tatum
 One gene - one enzyme
» Watson & Crick
 Architecture of DNA and implications for its replication
» Human Genome Project
 3 billion bp comes to life?
Post-Genomic Forecasting and PGx
»
Genetic diseases that are highly penetrant are rare
 Important but may not exemplars for geno-management of prevalent diseases
»
Common diseases are genetically complex
 Small contributions are conveyed by multiple genes
»
GWAS and massive parallel DNA sequencing may prove inadequate to
direct clinical management
 Identified key SNPs, haplotypes or DNA code are unlikely to guide individual
management decisions
 Population differences in linkage disequilibrium may diminish generalizability
»
Environmental factors contribute substantively through several mechanisms
to modulate inherited read-outs
 Delineation of specifics effectors is required (molecules, immune responses, etc)
»
Epigenomics appears essential for connecting potentiality
(genetically/genomically) with reality (at-risk, preclinical dz and manifest
dz)
 Elucidation of which/where (CpG, location), magnitude of effect (gene
Status of PGx
www.fda.gov/cder/genomics/genomic_biomarkers_table.htm
• Four drugs labeled as “Test Required”
• Eight drugs labeled as “Test Recommended”
• Thirteen drugs labeled as “Information Only”
State of PGx: Warfarin Illustration
Warfarin
CYP2C9
CYP2C9
ClinClin
Pharmacol
TherTher
77:2005
Pharmacol
77:2005
CYP2C9 Haplotypes
MOL PHARM 3: 2006
CYP2C9 Promoter
Illustration: Warfarin
Disease
INR
DVT/PE
2.0-3.0
Atrial Fibrillation
2.0-3.0
Myocardial Infarction
2.0-3.0
Mechanical Heart Valves
2.5-3.5
The State of PGx
www.fda.gov/cder/genomics/genomic_biomarkers_table.htm
1= Required; 2= Recommended
Warfarin Interactions
Increase INR or bleeding risk
Acetaminophen
Alcohol
Amiodarone
Anabolic Steroids
Antifungals
Aspirin and
Salicylates
Cephalosporins
Chloral Hydrate
Cimetidine
Clofibrate
Cranberry Juice (CYP2C9 inhibitor)
Danazol
Diflunisal
Disulfiram
Fluvoxamine
Ginkgo Biloba
Heparin
HMG CoA Reductase inhibitors
Isoniazid (INH)
Macrolides
Metronidazole
Nalidixic Acid
NSAIDs
Omeprazole
Paroxetine
Penicillin
Propafenone
Quinidine
Quinolones
Sulfinpyrazone
Tamoxifen
Tetracycline
Thyroid Hormone
Ticlopidine
Trimethoprim-Sulfamethoxazole Vitamin E
Decrease INR/ Increase clotting risk
American Ginseng
Barbiturates
Binding Resins
Carbamazepine (Tegretol)
Oral Contraceptives
Penicillin
Rifampin
St. John's Wort
Vitamin K
Warfarin Summary
» Two genes, CYP2C9 and VKORC, have
polymorphisms that affect activity and/or
expression
» CYP2C9 is potently upregulated by drugs and
other ingested chemicals
» Together these PGx contributions account for
~55% of inter-individual variability
Warfarin Dosing: A Complex Problem
» Metabolizing enzyme (CYP2C9): genetic variation
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(affecting substrate speciificity, Km or Vmax)
Metabolizing enzyme: regulated transcriptionally (affecting
absolute rate of mRNA production; linked to gene product
abundance)
Metabolizing enzyme: inhibited catalytically (Ki)
Drug target (VKORC): genetic variation (specificity, Km,
Vmax)
Drug target: regulated transcriptionally (rate of mRNA
synthesis; linked to gene product abundance)
Therefore, INR is a product of multiple dynamic effects
Estimation of Warfarin Dose with Clinical
and Pharmacogenetic Data
13 Variables
Required Patient Information
Age:
Sex:
Ethnicity:
Race:
Weight:
Height:
Smokes:
Liver Disease:
Indication: -Select-Atrial fibrillation/ Cardioembolic/ stroke/ Deep venous thrombosis/ Heart
failure/cardiomyopathy/ Heart valve replacement/ Hip fracture/ Hip
replacement/ Knee replacement/ Myocardial infarction/ Pulmonary
embolism/ Pulmonary hypertension
Baseline INR: Target INR:
CYP2C9 Genotype: CYP2C9*1/*1 (wildtype)CYP2C9*1/*2CYP2C9*2/*2CYP2C9*1/
*3CYP2C9*2/*3CYP2C9*3/*
VKORC1-1639/3673 Genotype:
Amiodarone/Cordarone® Dose: mg/day
Statin/HMG CoA Reductase Inhibitor: -Select-Atorvastatin/Lipitor®/Caduet®Fluvastatin/
Lescol®Lovastatin/Mevacor/Altoprev®/Advicor®Pravastatin/Pravachol®Rosuvastatin/
Crestor®Simvastatin/Zocor®/Vytorin®No statin/Any azole (eg. Fluconazole):
Sulfamethoxazole/Septra/Bactrim/Cotrim/Sulfatrim:
Where is PGx heading?
» PGx, while nascent, is derivative of genomics
» In the extreme, genomic information will be mined to
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derive an understanding of a restricted set of genes that
confer variability to drug metabolism and drug target
action
While likely to drive drug discovery and development and
biomarker validation it will likely have modest impact on
individualizing patient care
For greater precision a more comprehensive approach is
required incorporation genomic, epigenomic and
environmental assessments
Systems medicine is an example
Systems Medicine
» A holistic quantitative approach to defining the properties of a
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biological entity
Premised on Systems Biology, it examines the interactions of
elements (genes, proteins, metabolites and environmental
factors) dynamically
The elements are nodes, their interactions edges and their
behavior constitutes a network
Networks are measured quantitatively, modeled and their
“emergent” properties herald unanticipated biological
outcomes
The continuum between wellness and disease is not
discontinuous but rather characterized by a quantifiable
perturbation to a network
When sufficiently robust the network perturbation is manifest
somatically by a symptom or sign
Systems Medicine
Dynamic Networks
»
Elements (genes, proteins, etc) –
“nodes”--measurements!
»
Interactions between the elements –
“edges”--dynamic
»
Elements and their interactions are
affected by the context of other systems
within--cells and people AND the
environment
»
Interactions between/among elements
give rise to the system’s Emergent
properties
Modified from Lee Hood
Disease Arises from Perturbed Networks
dynamics of
pathophysiology
diagnosis
therapy
prevention
Non-Diseased
Courtesy of Lee Hood
Diseased
Getting There:
Epigenomics links inherited vulnerability to environment
The Central Dogma
Information Flow
DNA
RNA
Proteins
Metabolites
Biological Molecular Cast
But the dogma has changed!
Figures from: Alberts, Johnson, Lewis, Raff, Roberts, & Walter, Molecular Biology of the Cell, 4th Edition, Garland Science, New
York, NY (2002).
DNA can be Modified by Methylation
‘Abnormal’ DNA
What promotes non-coding epigenomic alteration?
Environment-Gene Interaction
DNA Methylation
Histone Acetylation
Transcription
Transcription
Ac
Ac
Nucleosomes
2
Environment
Ac
Ac
Ac
Ac
1,2 Epigenetic Changes
Gene
1 Me Me Me Me
Environment
Histone Acetylation
DNA Methylation
Transcription
Transcription
Is epigenomic methylation a dynamic process?
Global Change in Methylation in 7 years
Epigenomics and Medicine
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Genomic methylation appears highly dynamic in populations
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Environmental factors are overwhelmingly likely to be contributory to
such epigenomic changes
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Characterizing these epigenomic loci, their functional correlates,
implications for disease and its management are critical for the future
of clinical medicine
»
A full understanding of these processes will likely refine our
understanding of disease mechanisms, the selection of therapeutics,
measurements of responses and titration of dosing
As methylation and other epigenomic modifications are linked to
transcription this plasticity will be likely reflected by altered gene
expression AND altered biology
Training the Next Generation
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Design and implement curricula that include systems medicine
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First graduates: 2015
Develop training modules for clinical educators
Develop inpatient electives and outpatient modules
Develop new measures and utilize existing measures of the
performance of graduates
Develop GME and CME content
Thank you
A Strategy for Catalysis
 Structure a partnership comprising key stakeholders:
Industry, the academy and the relevant Federal agencies
 Focus on small but scaleable investigative, educational,
clinical and ethical objectives
 Leverage all available high quality digital data that has
application to human disease and its management
 Leverage supercomputing capacity through the DOE
funded national laboratories
 Commit to blending of open source and proprietary IP
 Develop infrastructure to support varied growth rates