Pharmacogenomics and Personalized Medicine

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Pharmacogenomics and Personalized Medicine
Michael D. Kane, PhD Associate Professor,
University Faculty Scholar, Graduate Education
Chair Department of Computer and Information
Technology College of Technology Lead Genomic
Scientist, Bindley Bioscience Center at Discovery
Park Purdue University West Lafayette, Indiana
47907 bioinformatics.tech.purdue.edu
Current Industry Positions Co-Founder Genomic
Guidance, LLC (Personalized Medicine, Information
Management) Co-Founder Broadband Antenna
Tracking Systems, Inc (Wireless Communications
Technology) Former Industry Positions Co-Founder
President Nucleico, LLC (Gene Expression
Profiling, Microarrays) VP of RD Genomic
Solutions, Inc (Biotechnology Instrumentation and
Software, Microarrays) Senior Scientist Pfizer
Pharmaceuticals (Molecular Technologies
Group) Scientific Advisor and Co-Inventor
Sensigen Diagnostics (Clinical HPV Detection)
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Bioinformatics Genomics
From Genetics to Data Management Systems
gtgi1924939embX98411.1HSMYOSIE Homo sapiens
partial mRNA for myosin-IF CAGGAGAAGCTGACCAGCCGCAA
GATGGACAGCCGCTGGGGCGGGCGCAGCGAGTCCATCAATGTGACCC
TCAACGTGGAGCAGGCAGCCTACACCCGTGATGCCCTGGCCAAGGGGCTC
TATGCCCGCCTCTTCGACTT CCTCGTGGAGGCCATCAACCGTGCTATGC
AGAAACCCCAGGAAGAGTACAGCATCGGTGTGCTGGACATT
TACGGCTTCGAGATCTTCCAGAAAAATGGCTTCGAGCAGTTTTGCATCAA
CTTCGTCAATGAGAAGCTGC AGCAAATCTTTATCGAACTTACCCTGAAG
GCCGAGCAGGAGGAGTATGTGCAGGAAGGCATCCGCTGGAC
TCCAATCCAGTACTTCAACAACAAGGTCGTCTGTGACCTCATCGAAAACA
AGCTGAGCCCCCCAGGCATC ATGAGCGTCTTGGACGACGTGTGCGCCAC
CATGCACGCCACGGGCGGGGGAGCAGACCAGACACTGCTGC
AGAAGCTGCAGGCGGCTGTGGGGACCCACGAGCATTTCAACAGCTGGAGC
GCCGGCTTCGTCATCCACCA CTACGCTGGCAAGGTCTCCTACGACGTCA
GCGGCTTCTGCGAGAGGAACCGAGACGTTCTCTTCTCCGAC
CTCATAGAGCTGATGCAGTCCAGTGACCAGGCCTTCCTCCGGATGCTCTT
CCCCGAGAAGCTGGATGGAG ACAAGAAGGGGCGCCCCAGCACCGCCGGC
TCCAAGATCAAGAAACAAGCCAACGACCTGGTGGCCACACT
GATGAGGTGCACACCCCACTACATCCGCTGCATCAAACCCAACGAGACCA
AGCACGCCCGAGACTGGGAG GAGAACAGAGTCCAGCACCAGGTGGAATA
CCTGGGCCTGAAGGAAAACATCAGGGTGCGCAGAGCCGGCT
TCGCCTACCGCCGCCAGTTCGCCAAATTCCTGCAGAGGTATGCCATTCTG
ACCCCCGAGACGTGGCCGCG GTGGCGTGGGGACGAACGCCAGGGCGTCC
AGCACCTGCTTCGGGCGGTCAACATGGAGCCCGACCAGTAC
CAGATGGGGAGCACCAAGGTCTTTGTCAAGAACCCAGAGTCGCTTTTCCT
CCTGGAGGAGGTGCGAGAGC GAAAGTTCGATGGCTTTGCCCGAACCATC
CAGAAGGCCTGGCGGCGCCACGTGGCTGTCCGGAAGTACGA
GGAGATGCGGGAGGAAGCTTCCAACATCCTGCTGAACAAGAAGGAGCGGA
GGCGCAACAGCATCAATCGG AACTTCGTCGGGGACTACCTGGGGCTGGA
GGAGCGGCCCGAGCTGCGTCAGTTCCTGGGCAAGAAGGAGC
GGGTGGACTTCGCCGATTCGGTCACCAAGTACGACCGCCGCTTCAAGCCC
ATCAAGCGGGACTTGATCCT GACGCCCAAGTGTGTGTATGTGATTGGGC
GAGAGAAGATGAAGAAGGGACCTGAGAAAGGTCCAGTGTGT
GAAATCTTGAAGAAGAAATTGGACATCCAGGCTCTGCGGGGGGTCTCCCT
CAGCACGCGACAGGACGACT TCTTCATCCTCCAAGAGGATGCCGCCGAC
AGCTTCCTGGAGAGCGTCTTCAAGACCGAGTTTGTCAGCCT
TCTGTGCAAGCGCTTCGAGGAGGCGACGCGGAGGCCCCTGCCCCTCACCT
TCAGCGACACACTACAGTTT CGGGTGAAGAAGGAGGGCTGGGGCGGTGG
CGGCACCCGCAGCGTCACCTTCTCCCGCGGCTTCGGCGACT
TGGCAGTGCTCAAGGTTGGCGGTCGGACCCTCACGGTCAGCGTGGGCGAT
GGGCTGCCCAAGAACTCCAA GCCTACCGGAAAGGGATTGGCCAAGGGTA
AACCTCGGAGGTCGTCCCAAGCCCCTACCCGGGCGGCCCCT
GGCGCCCCCCAAGGCATGGATCGAAATGGGGCCCCCCTCTGCCCACAGGG
GG
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GenBank Data GenBank Data GenBank Data
Year Base Pairs Sequences
1982 680,338 606
1983 2,274,029 2,427
1984 3,368,765 4,175
1985 5,204,420 5,700
1986 9,615,371 9,978
1987 15,514,776 14,584
1988 23,800,000 20,579
1989 34,762,585 28,791
1990 49,179,285 39,533
1991 71,947,426 55,627
1992 101,008,486 78,608
1993 157,152,442 143,492
1994 217,102,462 215,273
1995 384,939,485 555,694
1996 651,972,984 1,021,211
1997 1,160,300,687 1,765,847
1998 2,008,761,784 2,837,897
1999 3,841,163,011 4,864,570
2000 11,101,066,288 10,106,023
2001 15,849,921,438 14,976,310
2002 28,507,990,166 22,318,883
2003 36,553,368,485 30,968,418
2004 44,575,745,176 40,604,319
2005 56,037,734,462 52,016,762
2006 69,019,290,705 64,893,747
2007 83,874,179,730 80,388,382
2008 99,116,431,942 98,868,465
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Bioinformatics Genomics
Biomolecular Trends
Yeast Genome Human Genome Onion Genome Lily
Genome 1.2 x 107 BP 3.3 x 109 BP 15 x 109 BP 90 x
109 BP (1/275x Human) (1x) (5x
Human) (27x Human)
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Introduction to PharmacoGenomics
Single Nucleotide Polymorphisms (SNPs) are simple
changes (or differences) in the DNA sequence that
appear to have little or no impact on human
health. They represent 90 of all human genetic
variations. Genetically similar to a mutation,
but distinct in that a SNP is not causal to a
clinical disease or disorder (or at least not yet
causally linked, and not really applicable to
ages gt40 yrs old). Across the human genome we
average approximately 1 SNP for every 300 base
pairs of DNA (over one million known SNPs that
occur at a frequency of 1 or higher in the world
population). Important Consideration
Inheritance The appearance of deleterious
mutations during evolution tend to NOT be
inherited for obvious reasons, at least those
that affect growth, reproduction and
viability. and our modern existence is the
result of millions of years of tolerated (and
occasionally beneficial) changes in our genome,
which is most often evident in what we can and
cannot eat or consume (think evolutionary
pressure natural selection) Monomethyl
Hydrazine (in False Morel Mushrooms) Tylenol
Acetaminophen (Cats?) (many examples of toxins
in nature, many of them are presumably
synthesized to prevent consumption or predation
of the host plant or organism)
Modern drug discovery development falls outside
the tolerances toxicity that have resulted from
evolution, because most of these compounds have
NEVER been seen in nature.
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Adverse Drug Reactions
More than 770,000 patients die or sustain serious
injury every year in the U.S. from Adverse Drug
Reactions (ADRs). ADRs are therefore the 4th
leading cause of death in the United States and
are one of the leading, preventable public health
issues today. ADRs cost each hospital
approximately 5.6 million per year. In terms
of total health care dollars, ADRs cost the U.S.
health care system between 1.5 and 5.4 billion
per year. SNPs have been purposed to account for
24 of all ADRs.
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The Pharmacogenomics of Warfarin
When you ingest a drug, the drug is absorbed into
the circulatory system and is distributed
throughout the body. The drug is then available
to carry out its intended mechanism of action
(MOA). In the case of WARFARIN, it inhibits
Vitamin K Epoxide Reductase Complex 1 (VKORC1),
and reduces blood clotting. It is the largest
selling anticoagulant in the world, and the
leading case in support of Personalized
Medicine. Subsequently, the body has the
ability to eliminate the drug from the body
through drug metabolism, which is primarily
carried out in the liver. WARFARIN is metabolized
primarily by the oxidative liver enzyme CYP2C9,
which basically adds an oxygen group to the
WARFARIN structure thereby inactivating its MOA
and increasing its likelihood of elimination from
the body via the kidneys (urine). For this
reason, drug tests that utilize urine a sample
source often look for the metabolite of the
drug in the urine, rather than the ingested
drug. IMPORTANT If you are prescribed WARFARIN,
you have a condition that generates potentially
life-threatening blood clots. If you are dosed
with too much WARFARIN you could die from
complications due to internal bleeding, yet if
you are dosed with too little WARFARIN you may be
in danger of serious consequences due to
circulating embolism.
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Go to www.genescription.com Genescription is a
free, online training program in Personalized
Medicine for instructors and healthcare
professionals. (developed through a grant from
Microsoft External Research)
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Examples of Clinically-Relevant SNPs
From Kane, et al. Drug Safety Assurance through
Clinical Genotyping Near-Term Considerations for
a System-Wide Implementation of Personalized
Medicine. Personalized Medicine 5(4) 387-397
(2008)
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Evidence suggests that Healthcare will be a
primary influence on the US economy for the next
50 years. The Workforce 2015 Strategy Trumps
Shortage describes how hospitals face the
overlapping challenges of attracting and
retaining replacements for retiring workers,
expanding its workforce to care for an aging
population, the greater demand for information
technology professionals while coping with
significant changes in healthcare delivery. The
Global Healthcare Information Technology (2009 -
2014) report states that the current healthcare
information technology market is estimated to be
53.8 billion. Where do YOU see professional,
commercial, and entrepreneurial opportunities in
this emerging area of healthcare?
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Clinical Genotyping Workflow in Healthcare
From Kane, et al. Drug Safety Assurance through
Clinical Genotyping Near-Term Considerations for
a System-Wide Implementation of Personalized
Medicine. Personalized Medicine 5(4) 387-397
(2008)
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Clinical Genotyping Workflow in Healthcare
From Kane, et al. Drug Safety Assurance through
Clinical Genotyping Near-Term Considerations for
a System-Wide Implementation of Personalized
Medicine. Personalized Medicine 5(4) 387-397
(2008)
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Considerations for Clinical Genotyping Data
Management and User Interface Design and Content
in Healthcare
From Kane, et al. Drug Safety Assurance through
Clinical Genotyping Near-Term Considerations for
a System-Wide Implementation of Personalized
Medicine. Personalized Medicine 5(4) 387-397
(2008)
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QUESTIONS?