Biomedical Informatics and Interdisciplinary Research

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Clinical Genotyping and Personalized Medicine
Michael D. Kane, PhD (1) Associate Professor of
Bioinformatics (2) University Faculty Scholar (3)
Chair of Graduate Education Department of
Computer and Information Technology (4) Lead
Genomic Scientist Bindley Bioscience Center at
Discovery Park Purdue University West Lafayette,
Indiana, USA bioinformatics.tech.purdue.edu
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At the current rate of genomic sequencing
worldwide, a new gene sequence is derived every
1.7 seconds! equivalent to 500 DNA base pairs
every second of every day!
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Genetic Variance
Single Nucleotide Polymorphisms (SNPs) are simple
changes (or differences) in the DNA sequence that
may 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.
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Genetic Variance
Important Consideration Inheritance The
appearance of deleterious mutations during
evolution tend to NOT be inherited for obvious
reasons (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 natural
products we can and cannot eat or consume (think
evolutionary pressure natural
selection) Monomethyl Hydrazine (in False
Morel Mushrooms) (there are many examples of
toxins in nature, many of them are presumably
synthesized to prevent consumption or predation
of the host plant or organism) Tylenol
Acetaminophen (Cats?)
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, and natural-based
pharmaceuticals are concentrated and enriched for
dosing purposes.
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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 typically the 5th leading cause of
  death in the United States and are one of the
  leading, preventable public health issues today.
• In terms of total health care dollars, ADRs cost
  the U.S. health care system between 1.5 and 5.4
  billion per year.
• It is estimated that human genetic variation
  (SNPs) have been account for approximately 30 of
  all ADRs.

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Pharmacogenomics and Personalized Medicine
Pharmacogenomics involves genetic differences in
the human population that alter the safety and
efficacy of drugs (from the normal or typical
patient). For the healthcare consumer, most of
these genetic differences have an effect on (1)
drug metabolism (pharmacokinetics) or (2) drug
action (pharmacodynamics). Personalized Medicine
involves understanding how some genetic markers
impact drug safety and efficacy, and PREDICTING
how a patient will respond to a specific
drug/dose (based on the patients genetic
profile).
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Pharmacogenomics and Personalized Medicine

• Drug Metabolism and Personalized Medicine
  Oxidative enzymatic breakdown of the dosed
  drug, primarily in the liver.
• Normal Metabolism The drug is cleared from the
  body at the rate established by the
  pharmaceutical manufacturer.
• Ultra Metabolism The patient harbors a genetic
  allele that INCREASES the rate of drug metabolism
  and clearance.
• Poor Metabolism The patient harbors a genetic
  allele that DECREASES the rate of drug metabolism
  and clearance.

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Pharmacogenomics and Personalized Medicine
1 in 5 people harbor a SNP that alters the drug
metabolism or drug activity of at least one FDA
approved drug. The effect of this genetic
variation in the population does not always
represent a serious risk to the patient, but may
effect patient compliance and other side
effects related issues that negatively impact
health outcomes.
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Pharmacogenomics and Personalized Medicine
Warfarin (Coumadin) Anticoagulation. EXAMPLE If
you are prescribed WARFARIN, you have a condition
that may generate potentially life-threatening
blood clots. If you are dosed with too much
WARFARIN you could experience serious
complications due to internal bleeding, yet if
you are dosed with too little WARFARIN you may be
in danger of serious consequences associated with
circulating emboli due to excessive blot clotting.
Warfarin Drug Action (circulator system) Vitamin
K Epoxide Reductase Complex 1 (VKORC1) Inhibitor
Warfarin Metabolism (hepatic) CYP2C9 to
6-hydroxywarfain
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Pharmacogenomics and Personalized Medicine

• GENESCRIPTION was developed as an educational
  tool that models the FUTURE of applied
  personalized medicine.
• The online portal models a drug dispensing
  environment (pharmacist) where the user is
  presented with a patient that has
• DNA screened to identify any SNPs related to drug
  safety and efficacy.
• Prescribed a drug that is affected by a SNP
  related to drug safety and efficacy.
• Provides predictive information regarding the
  safety and efficacy of the prescribed drug in the
  patient.

www.genescription.com Genescription is a free,
online instructional utility available to the
public, and can be accessed and utilized by
anyone with an internet connection.
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Dosing curve of a 10 mg oral dose in a normal
metabolizer
From www.genescription.com
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Dosing curve of a 10 mg oral dose in a poor
metabolizer
From www.genescription.com
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Dosing curve of a 10 mg oral dose of Warfarin in
a poor metabolizer
From www.genescription.com
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Dosing curve of a 10 mg oral dose of Warfarin in
a VKORC1-SNP Patient
From www.genescription.com