4. INTRODUCTION
Pharmacogenomics deals with the influence of genetic
variation on drug response by co-relating gene
expression or polymorphism with a drug’s efficacy
or toxicity
It intends to identify individuals who are either more
likely or less likely to respond to a drug, as well as
those who require altered dose of certain drugs
5. GENETICS VS. GENOMICS
Pharmacogenetics is often a study of the variations in
a targeted gene, or group of functionally related
genes for variability in drug response
Refers to how variation in one single gene
influences the response to a single drug
Pharmacogenomics is the use of genetic information
to guide the choice of drug and dose on an
individual basis.
Broader term, which studies how all of the genes (the
genome) can influence responses to drugs
8. THE FOUNDATION OF PHARMACOGENOMICS:
Mutation: difference in the DNA code that occurs in
less than 1% of population
Often associated with rare diseases
Cystic fibrosis, sickle cell anemia, Huntington’s disease
Polymorphism: difference in the DNA code that
occurs in more than 1% of the population
A single polymorphism is less likely to be the main cause of
a disease
Polymorphisms often have no visible clinical impact
9. A Single Nucleotide Polymorphism (SNP) are DNA
sequence variation that occurs when a single
nucleotide in the genome sequence is altered.
Occur in at least 1% of the population and make up
about 90% of all human genetic variation
11. POLYMORPHISMS
May result in a different amino acid or stop codon
May result in a change in protein function
No effect
Genetic polymorphisms in drug-metabolizing
enzymes, transporters, receptors, and other drug
targets inter individual differences in the efficacy
and toxicity of many medications
13. PERSONALIZED MEDICINE
It refers to an approach of clinical practice where a
particular treatment is not chosen based on the
‘average patient’ but on characteristic of an individual
patient
16. POLYMORPHISM OF ENZYMES & DRUG
METABOLISM
The cytochrome P-450 mixed-function oxidase (CYP)
N-acetyltransferase (NAT1 and NAT2)
Thiopurine-S-methyltransferase (TPMT)
Uridine-5 diphosphate glucuronyl transferase-
Polymorphisms of UGT1A1 and UGT2B7 play important
roles in the phase II metabolism of certain drugs.
17.
18. Cytochrome P450 enzymes
a) CYP2D6
Metabolism of 20-25% of marketed drugs
Polymorphism best studied
Drugs: SSRI, TCA, beta blockers, antipsychotics
b) CYP2C19
More than 20 polymorphism reported
Drugs: PPI, Mephenytoin,N-demethylation of TCA(
amitryp, clomipramine, nortryp)
Proguanil to cycloguanil
19. c) CYP 2C9
Biotransformation of warfarin, phenytoin, fluvastatin,
several NSAIDS, Antidiabetics
c) CYP3A4/5
Most abundant
Seen in human liver
Metabolism of more than 50% of drugs
20 variants identified
Eg: CYP3A4*16, CYP3A4*2, CYP3A4*7
22. ROCHE AMPLICHIP P450
TEST
The Roche AmpliChip CYP450 Test is intended to
identify a patient's CYP2D6 and CYP2C19 genotype
from genomic DNA extracted from a whole blood
sample
An aid to clinicians in determining therapeutic
strategy and treatment dose for therapeutics
25. Insulin resistance
Polygenic[ Ark-I, Atl, Minn]
Insulin receptor α subunit
Arrhythmia with antiarrhythmics
Torsades de pointes
Genetic abnormality in k+ channel(polymorphism)
Resistance to drug effects
Vit D resistance rickets
Coumarin resistance( polymorphism of vit K reductase)
26.
27. Drug targets
Haloperidol & D2 receptor
HER 2 & trastuzumab
Drug development
Identifies patient group who would have high or
low likelihood of responding to the agent
EGFR mutation & response to gefitinib
HLA polymorphism HLA-B*5701 & hypersensitivity
with Abacavir
APOE & Tacrine in AD
28.
29. LIMITATIONS:
Many genes are involved in drug action, making the
drug target very difficult
Insufficient validation of study results
Identification of small inter-individual variation in
everyone’s gene is very difficult
Expensive
Ethical issues
