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Pharmacogenetics/Pharmacogenomics
Outline
• Introduction
 Differential drug efficacy
 People react differently to drugs
Why does drug response vary?
 Potential causes of variability in drug effects
 Genetic variation
Pharmacogenetics
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What is Pharmacogenetics?
Pharmacogenetics VS. Pharmacogenomics
Genetic variation and drug response
Determinants of Drug Efficacy and Toxicity
Examples
Same symptoms,
Same findings,
Same disease?
Different patients
Same drug
Same dose
Differential drug efficacy
At a recommended prescribed dosage—
a drug is efficient in most.
Lack of efficacy
not efficient in others.
harmful in a few.
Unexpected side-effects
People react differently to drugs
Toxic responders
Non-responders
Responders
“One size does not fit all …”
Patients with drug toxicity
Ethnicity
Age
Pregnancy
Genetic factors
Disease
Drug interactions
Patient population with
same disease phenotype
Patients with non-response
to drug therapy
Patients with normal response
to drug therapy
Why does drug response vary?
Genetic variation
• Genetic variation
• Primarily two types of genetic mutation events
create all forms of variations:
 Single base mutation which substitutes one nucleotide
for another
--Single nucleotide polymorphisms (SNPs)
 Insertion or deletion of one or more nucleotide(s)
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--Tandem Repeat Polymorphisms
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--Insertion/Deletion Polymorphisms
• Polymorphism: A genetic variation that is observed at a
frequency of >1% in a population
Single nucleotide polymorphisms (SNPs)
• SNPs are single base pair positions in genomic DNA at which
different sequence alternatives (alleles) exist wherein the least
frequent allele has an abundance of 1% or greater.
• SNP
might change
the DNA sequence
• SNPs are the most commonly occurring genetic differences.
Single nucleotide polymorphisms (SNPs)
• SNPs are very common in the human population.
• Between any two people, there is an average of one SNP every
~1250 bases.
• Most of these have no phenotypic effect
– estimate that 3.2 million SNPs in genome
– only <1% of all human SNPs impact protein function (lots of
in “non-coding regions”)
• Some are alleles of genes
Insertion or deletion of one or more nucleotide(s)
Tandem Repeat Polymorphisms
• Tandem repeats or variable number of tandem repeats
(VNTR) are a very common class of polymorphism,
consisting of variable length of sequence motifs that are
repeated in tandem in a variable copy number.
• Can affect transcript amount
• Based on the size of the tandem repeat units:
 Microsatellites or Short Tandem Repeat (STR)
• repeat unit: 1-6 (dinucleotide repeat: TATA- in
UCIT1A1 (glucuronosil transferase) promoter)
 Minisatellites
• repeat unit: 14-100
Insertion or deletion of one or more nucleotide(s)
Insertion/Deletion Polymorphisms
Insertion/Deletion (INDEL) polymorphisms are quite common
and widely distributed throughout the human genome
• Larger insertions/deletions that add or substract amino acids
(CBS-Cystathionine β-synthase, common 68 bp INDEl
polymorphism which affect folate level)
• Gene duplication – stably transmitted inherited germline gene
replication that causes increased protein exp. and activity
(CytochromeP4502D6, up to 13 genes)
• Large Deletions – gene deletions, result in complete loss of
protein production (entire GSTM1-glutathione-S-transferase,
homozygous null individuals have only 50% of glutathione
conjugating capacity of those with at least one copy of the gene)
Pharmacokinetics and Pharmacodynamics
Pharmacogenetics
The study of variations in genes that determine
an individual’s response to drug therapy.
Genetic Polymorphism:
SNPs; INDEL; VNTRs
Potential Target Genes are those that encode:
Drug-metabolizing enzymes
Transporters
Drug targets
Common variation in DNA sequence
(i.e. in >1% of population)
Example
A simple test, the urinary metabolic ratio, after administration of a probe
drug can identify the extensive metabolizer and the poor metabolizer
phenotype
CYP2D6
THE DEBRISOQUINE-SPARTEINE POLYMORPHISM
1977, physicians at St. Mary’s Hospital Medical School in London –
a volunteer’s hypotensive response to debrisoquine, a sympatholytic
antihypertensive drug, was markedly increased because of impaired metabolism.
Group of Germany physicians independently observed increased side effects
associated with decreased oxidative metabolism of sparteine, an alkaloid drug
with antiarrhythmic actions .
Family studies revealed that both oxidative metabolic reactions are under
monogenic control and that poor metabolizers are homozygous for a recessive
allele.
A simple test, the urinary metabolic ratio (MR) →5 to 10% of individuals in white
populations are of the poor-metabolizer phenotype, compared with only
1 to 2% in Asian populations
CONSEQUENCES OF THE
DEFICIENT CYP2D6
Responsible for metabolism of 15-25% of all medicines in use
Poor-metabolizer
(7 variants of low-activity alleles)
1. Increased risk of toxicity of antidepressants or antipsychotics
(catabolized by the enzyme drugs)
2. Lack of analgesic effects of codeine (anabolized by the enzyme)
3. Exaggerated response to
Ultra-rapid-metabolizer
(stable gene duplication, up to 13 active genes)
3. Extremely rapid clearance and thus inefficacy of antidepressants
Pharmacogenetics in Clinical Practice
 20-40% of patients benefit from an approved drug
 70-80% of drug candidates fail in clinical trials
 Many approved drugs removed from the market due to
adverse drug effects
• The use of DNA sequence information (genome-wide
approach) to measure and predict the reaction of individuals
to drugs.
 Personalized drugs
 Faster clinical trials
 Less drug side effects
Pharmacogenetics and Pharmacogenomics
Knoweledge Base (PharmGKB)
Genotype and phenotype data related to drug response
WWW.PHARMGKB.ORG
(NIH Sponsored Research Network And
Knowledge Database)