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
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!
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.
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.
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.
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 patient’s genetic profile).
Pharmacogenomics and Personalized Medicine
Drug Metabolism and Personalized Medicine: Oxidative enzymatic
“breakdown” of the dosed drug, primarily in the liver.
1) Normal Metabolism: The drug is cleared from the body at the rate
established by the pharmaceutical manufacturer.
2) Ultra Metabolism: The patient harbors a genetic allele that
INCREASES the rate of drug metabolism and clearance.
3) Poor Metabolism: The patient harbors a genetic allele that
DECREASES the rate of drug metabolism and clearance.
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.
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 Metabolism (hepatic)
CYP2C9 to 6-hydroxywarfain
Warfarin Drug Action (circulator system)
Vitamin K Epoxide Reductase Complex 1
(VKORC1) Inhibitor
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:
1) DNA screened to identify any SNPs related to drug safety and efficacy.
2) Prescribed a drug that is affected by a SNP related to drug safety and efficacy.
3) 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.
Dosing curve of a 10 mg oral dose in a “normal” metabolizer
From: www.genescription.com
Dosing curve of a 10 mg oral dose in a “poor” metabolizer
From: www.genescription.com
Dosing curve of a 10 mg oral dose of Warfarin in a “poor” metabolizer
From: www.genescription.com
Dosing curve of a 10 mg oral dose of Warfarin in a VKORC1-SNP Patient
From: www.genescription.com