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PHARMACOGENOMICS ANALYSIS
LABORATORY
Cooperative Studies Program (CSP)
Office of Research & Development,
Department of Veterans Affairs
Central Arkansas Veterans
Healthcare System (CAVHS)
Little Rock, AR
CSP ORGANIZATION
VETERANS HEALTH ADMIN
Office of Research &
Development
Biomedical
Laboratory
R&D
Clinical
Science
R&D
Health
Services
R&D
Rehabilitation
R&D
Cooperative Studies
Program
Pharmacogenomics
Analysis Laboratory (PAL)
CSP MISSION
To advance the health and care of Veterans
through collaborative research studies that
produce innovative and effective solutions to
national healthcare problems.
CSP OVERVIEW
• CSP is a national infrastructure for sponsoring, developing
& executing:



Multi-site clinical trials
Epidemiological & population research
Genomics research
• First Cooperative Study conducted in 1940s on
streptomycin for treating tuberculosis in WWII veterans

Program formally established in 1972
• Over 175 clinical trials and observational studies
completed including landmark studies in cardiovascular
disease / cardiovascular surgery, infectious diseases,
surgery, gastroenterology, mental health, oncology, and
endocrinology.
CSP CENTER LOCATIONS
Seattle,
WA
Boston,
MA
West Haven,
CT
Hines,
IL
Palo
Alto, CA
Little Rock, AR
Albuquerque,
NM
Perry Point, MD
Washington, DC
Durham,
NC
VA Genomic Medicine Program
• In 2006, the Department of Veterans Affairs
launched the Genomic Medicine Program:
to examine the potential of emerging
genomic technologies
 to optimize medical care for veterans
 to enhance the development of tests and
treatments for relevant diseases

Genomic Medicine Program Con’t
• Genomic Medicine Program Advisory
Committee
• Veterans’ Consultation Project

83% supported; 71% willing to participate
• Scientific Projects
 Investigator-initiated
 Large scale cohorts (SMI, PTSD, ALS)
 Million Veteran Program (non-disease
based)
Infrastructure Development

Expansion of Biorepository



IT and Informatics


CSP DNA Bank (~30,000 samples)
Expansion to ~4M; robotic store; automation
Genomic Information System for Integrated
Sciences(GenISIS)
Pharmacogenomics Laboratory (PAL)

Established in 2007
Pharmacogenomics Analysis
Laboratory (PAL)
•CLIA88 approved laboratory with capacity to
conduct medium to high throughput genotyping
and gene expression assays.
•Support ongoing and future pharmacogenomics
observational studies and clinical trials.
•Improving treatment of most illnesses by
reducing toxicity and increasing efficacy of drugs
by facilitating optimal treatment selection,
appropriate dose individualization, and drug
discovery.
PAL Organizational FlowChart
DIRECTOR
Steven A. Schichman, M.D., Ph.D.
LABORATORY
MANAGER
Angie Stone, B.S.
Weleetka Carter, Maria Winters, Angie Stone
Dr. Steven A.
Schichman
PAL Director
PROJECT MANAGER
Maria Winters, M.P.H.
PROJECT
COORDINATOR
Weleetka Carter, B.S.
Gene Expression
RNA Purification &
Quantification
NanoDrop UV/Vis, Agilent Bioanalyzer,
Biotek Plate Reader (RiboGreen
Fluorescence)
TaqMan RNAse P
ABI Taqman, Illumina iScan & BeadXpress
miRNA
miRNA
ABI Taqman
SNP Genotyping
DNA Purification &
Quantification
NanoDrop UV/Vis, Agilent Bioanalyzer,
Biotek Plate Reader (PicoGreen
Fluorescence)
TaqMan RNAse P
Protein Quantification
PAL
Data Analysis & Final
Reports
ABI Taqman, Illumina iScan & BeadXpress
Copy Number,
EpiGenetic Events
ABI Taqman, Illumina iScan & BeadXpress
Protein Analysis
NanoDrop UV/Vis, Agilent Bioanalyzer
Illumina BeadXpress
CAVHS
ABI 7900HT TaqMan System
The ABI 7900HT (Applied Biosystems, Inc., Foster City,
CA) is a PCR-based, real-time thermal cycling
instrument with fluorescence detection for low-tomoderate throughput genotyping and gene expression
Applications Supported by
ABI7900HT TaqMan
Genotyping by Allelic Discrimination
Gene Expression
Real-Time Quantification
Copy Number Variation
Illumina iScan System
•iScan microarray scanner (Illumina, Inc., San Diego, CA) is
a confocal laser scanner with dual fluorescent channels for
imaging Illumina’s array-based genetic analysis products.
•Automation with the AutoLoader2 provides high-throughput
scanning.
iScan Applications
Copy Number Variation: Discovery and Analysis
BeadChip Genotyping Array: Whole-Genome SNP
Analyses, Cytogenetic Analysis, Linkage Profiling
Gene Expression
Treatment_ AVG_Signal
30000
20000
10000
0
0
10000
20000
30000
Cont rol_AVG_Signal
Whole-Genome Expression Profiling, Differential Gene Expression, microRNA profiling
Whole-Genome Methylation Analyses, Differential
Methylation, Dendrograms (Cluster Analysis)
Illumina iScan Array
Products
Illumina BeadXpress System
Illumina’s BeadXpress Reader is a dual-color laser
detection system for custom low- to mid-plex
genotyping, methylation analysis, SNP detection and
protein screening.
ADME Core Panel for
Pharmacogenetic Genotyping
Investigate genetic
associations to drug
• Response
• Dosing
• Safety
► Personalized Medicine
►
*Absorption, Distribution,
Metabolism, and Excretion
VeraCode ADME Core Panel
ADME Core (34 genes, 184 markers)
ABCB1
CYP2C9
NAT1
SULT1A1
ABCC2
CYP2D6
NAT2
TPMT
ABCG2
CYP2E1
SLC15A2
UGT1A1
CYP1A1
CYP3A4
SLC22A1
UGT2B15
CYP1A2
CYP3A5
SLC22A2
UGT2B17
CYP2A6
DPYD
SLC22A6
UGT2B7
CYP2B6
GSTM1
SLCO1B1
VKORC1
CYP2C19
GSTP1
SLCO1B3
CYP2C8
GSTT1
SLCO2B1
>95% Pharma ADME Core List: www.pharmaadme.org
IT Requirements
• Large capacity Terabyte Servers
• 64-Bit Computers
• GenomeStudio Software Suite
• Statistical Discovery Software
CSP Study Update
CSP 500b: Genetic Epidemiology of Amyotrophic
Lateral Sclerosis (ALS)
•
GWAS analysis by Affymetrix & Illumina platforms
completed
•
• 1200 ALS patients ; 400 Controls
Analysis of data ongoing at the Durham VA and Duke University
Principal Investigators in CSP500b:
Durham VAMC and Duke University Medical Center, NC
Eugene Z. Oddone, M.D., M.H.S.
Silke Schmidt, Ph.D.
Dawn Provenzale, M.D., M.S.
Michael A. Hauser, Ph.D.
Boston MAVERIC and Tissue Core Biorepository, MA
Mary Brophy, M.D.
Donald E. Humphries, Ph.D.
Durham VA Medical Center
North Carolina
Summary
• PAL serves as a national VA resource
for various molecular, genetic and
genomic analyses (low to high
throughput)
• Isolation to data analysis
• CLIA certified