Pharmacogenetics

1. Introduction to Pharmacogenomics
Delelegn G. (B.Pharm, MSc in Pharmacology)
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2. Learning contents
• Basic concepts of pharmacogenetics vs Pharmacogenomics
• Historical Perspectives of pharmacogenomics
• Scope and application of pharmacogenomics
• Introduction to human genome
• Gene expression and control of gene expression
• Genetic variation
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3. Introduction
All patients with same diagnosis
1
2
Responders and patients
not predisposed to toxicity
Non-responders and
Toxic responders
Treat with alternative drug or dose
Treat with conventional drug
or dose
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4. Intro…..
Pharmacogenetics Vs Pharmacogenomics ?
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5. Intro…..…
• Pharmacogenetics
– Study of how genetic differences in a SINGLE gene
influence variability in drug response (i.e., efficacy and
toxicity)
• Pharmacogenomics
– Study of how genetic (genome) differences in
MULTIPLE genes influence variability in drug response
(i.e., efficacy and toxicity)
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6. Intro…
• The term pharmacogenetics often is used interchangeably with
the term pharmacogenomics
• However, pharmacogenetics generally refers to monogenetic
variants that affect drug response, whereas pharmacogenomics
refers to the entire spectrum of genes that interact to determine
drug efficacy and safety
 In conclusion both have been defined as the study of variability
in drug response due to heredity.
Genetic polymorphism
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7. Intro…
Generally pharmacogenomics deals on:
• DNA sequence variation Vs Pharmacokinetic/dynamic inter individual
variation on drug
 metabolizing enzyme
 transporter
 receptor and related pathway proteins
• “Correlating heritable genetic variation to drug response”
Ultimate goal
• understand how someone's genetic make-up determines, how well a medicine
works in his or her body, as well as what side effects are likely to occur.
• “Right medicine for the right patient”
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8. Historical Perspectives
• Friedrich Vogel coined the term “pharmacogenetics” (1959)
define a new science aimed to study the influence of
inherited factors on drug response variability through
genetic and pharmacological knowledge and methods
• Evidence for a genetic basis of clinical syndromes associated
with
 when antimalarial drugs (e.g. primaquine): haemolytic
anemia in patients with G6PD deficiency ‘1950s)
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9. Historical …
• The discovery of the first pharmacogenetic deficiency at the
molecular level occurred in the 1980s when
Gonzales and his colleagues cloned the CYP2D6 gene and
characterized the genetic polymorphism responsible for
the decreased expression of the CYP2D6 enzyme
Decreased expression levels of CYP2D6:
 ↓mRNA were previously identified as responsible
for reduced metabolism and adverse response to
debrisoquine
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10. Historical …
• This research gave rise to several studies based on the use of
efficient molecular technologies linked
to classical pharmacological phenotypization
genetic population studies
– Resulted in: the identification of several polymorphisms in
genes involved in drug metabolism and mechanism of action
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11. Table: Some important milestones in the history of pharmacogenomics
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12. Historical …
Nowadays it has already been possible
• to identify several variations in the structure of genes codifying
enzymes of drug metabolism
transporter proteins or
target proteins (receptors, ion channels, enzymes) of drugs
• And to correlate these gene variations to inter-individual
variations in the response to xenobiotics.
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13. Historical …
• Many genetic factors, predictive of toxicity and response to
pharmacological treatments, have thus been identified
• Nowadays, pharmacogenetic and pharmacogenomic tests may
help clinicians to choose the best treatment and safest dose
for each patient.
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14. Scope and application of pharmacogenomics
pharmacogenomics have the following applications:
– Development of drugs that maximise therapeutic effects
but decrease damage to nearby healthy cells
– Prescription of drugs based on a patient’s genetic profile
– More accurate methods of determining dosages
– Development of vaccines made of genetic material
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15. Scope and application ……
– Detect diseases at an earlier stage, when it is easier to
treat effectively
– Increase patient compliance with therapy
– Improve the selection of targets for drug discovery and
reduce the time, cost, and failure rate of clinical trials
– Reduce the overall cost of healthcare
Treatment individualization
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16. Economic aspects of Pharmacogenetics
• Pharmacoeconomically, pharmacogenomics is highly important to
reduce health care cost via
decreasing the number of unnecessary screening and diagnostic
tests ordered
identifying individuals genetically at high risk for the common
diseases of adulthood (hypertension, heart disease, cancer and
diabetes), allowing for extensive environmental intervention
leading to more rapid recovery since the correct medication and
dosing for the individual patient will lead to the end of “trial and
error” prescribing
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17. Introduction to human genome
• Genes are segments of deoxyribonucleic acid (DNA) that
contain the code for a specific protein that functions in one or
more types of cells in the body
• Genes are contained in chromosomes, which are mainly in
the cell nucleus
• A chromosome contains hundreds to thousands of genes
• Every human cell contains 23 pairs of chromosomes, for a
total of 46 chromosomes.
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18. Human genome…..
• Genotype is a complete set of instructions on how that person’s
body synthesizes proteins and thus how that body is supposed to
be built and function
• The phenotype is the actual structure and function of a person’s
body
 For example, hair color, weight, or the presence or absence of
a disease
• During DNA replication, and subsequent inheritance, it is often
said that what is passed from one generation to the next is the
“information” in the genes
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20. Gene expression
• Gene expression is the process by which the genetic code
(nucleotide sequence) of a gene is used to direct protein synthesis
The process involves two main stages:
• Transcription: the production of mRNA by the enzyme RNA
polymerase, and the processing of the resulting mRNA molecule
• Translation: the use of mRNA to direct protein synthesis
 Some genes are responsible for the production of other forms of RNA that
play a role in translation, including tRNA and rRNA
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22. Control of gene expression
• Controlling gene expression is often accomplished by
controlling transcription initiation
• Regulatory proteins bind to DNA to either block or stimulate
transcription, depending on how they interact with RNA
polymerase
Control of transcription initiation can be:
• Positive control – increases transcription when activators bind
DNA
• Negative control – reduces transcription when repressors bind
to DNA regulatory regions called operators
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23. Genetic variation
• Genetic variation is the d/ce in the nucleotide sequence of DNA
b/n individuals of a species
• Mutation is the main source of genetic variation
• This variation, which is called a polymorphism, is largely
responsible for differences between how humans respond to
drugs
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24. Genetic variation ……
Molecular mechanisms of Mutation
• The most common genetic variants(90%) are single nucleotide
polymorphism substitutions (SNPs; pronounced “snips”).
 Where one nucleotide replaced by an other
 occur approximately once in every 100 to 300 base pairs
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25. Genetic variation ……
Examples of genetic variants include the following:
• Insertion–deletion (indel)polymorphisms
 nucleotide or nucleotide sequence is either added to or deleted
from a DNA sequence
• Tandem repeats
 a nucleotide sequence repeats in tandem (e.g., if “AG” is the
nucleotide repeat unit, “AGAGAGAGAG” is a five-tandem
repeat)
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26. Genetic variation ……
• Frameshift mutation
 there is an insertion/deletion polymorphism
 the number of nucleotides added or lost is not a multiple of
three
 resulting in disruption of the gene’s reading frame
• Premature stop codon polymorphisms
 there is premature termination of the polypeptide chain by a
stop codon
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27. Genetic variation ……
• Causes of mutation
- Errors in replication and recombination
- Chemical mutagenes: dyes, benzene, pesticides
- Irradiation: UV light, X-rays
- Spontaneous changes: deamination or depurination
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