Genetics and Pharmacogenomics

Student: Azizullah Mukhtar

Outlines
• Genetics
• Gene
• Alleles
• Phenotype
• Genotype
• Chromosomes
• Nucleotides
• Codon
• Genetical Variations
• Pharmacogenomics
• Pharmacogentics
• Gene Therapy
 Genetics
• Genetics – study of how traits are passed from parent
to offspring
Gene
• Traits are determined by the genes on the
chromosomes. A gene is a segment of DNA that
determines a trait.
• Chromosomes come in homologous pairs, thus genes
come in pairs.
Homologous pairs – matching genes – one from female
parent and one from male parent
• Example: Humans have 46 chromosomes or 23 pairs.
One set from dad – 23 in sperm
One from mom – 23 in egg
• One pair of Homologous Chromosomes:
Gene for eye
color (blue eyes)

Homologous pair
of chromosomes

Gene for eye color

(brown eyes)

Alleles – different genes (possibilities) for the same trait –

ex: blue eyes or brown eyes
Dominant and Recessive Genes
• Gene that prevents the other gene from “showing” –
dominant
• Gene that does NOT “show” even though it is present –
recessive
• Symbol – Dominant gene – upper case letter – T
Recessive gene – lower case letter – t

Recessive
Dominant
color
color
• Both genes of a pair are the same –
homozygous or purebred
TT – homozygous dominant
tt – homozygous recessive

• One dominant and one recessive gene –

heterozygous or hybrid
Tt – heterozygous

BB – Black bb – White
Bb – Black w/
white gene
Genotype and Phenotype
• Combination of genes an organism has (actual gene
makeup) – genotype
Ex: TT, Tt, tt
• Physical appearance resulting from gene make-up –
phenotype
Ex: hitchhiker’s thumb or straight thumb
Chromosomes

Chromosomes are thread-like

structures located inside the
nucleus of animal and plant
cells. Each chromosome is made
of protein and a single molecule
of deoxyribonucleic acid (DNA).
Passed from parents to offspring,
DNA contains the specific
instructions that make each type
of living creature unique
A codon is a DNA or RNA sequence of three nucleotides (a
trinucleotide) that forms a unit of genomic information encoding a
particular amino acid or signaling the termination of protein
synthesis (stop signals). There are 64 different codons: 61 specify
amino acids and 3 are used as stop signals.

Nucleotides are organic molecules

composed of a nitrogenous base, a
pentose sugar and a phosphate.
They serve as monomeric units of
the nucleic acid polymers –
deoxyribonucleic acid and
ribonucleic acid, both of which are
essential biomolecules within all
life-forms on Earth.
GENE THERAPY
Gene Therapy
Gene therapy = Introduction of normal genes into
cells that contain defective genes to reconstitute a
missing protein product

It is an approach to treat, cure, or ultimately

prevent
disease by changing the expression of a persons
genes.
Illustrated Diagram
TYPES: Somatic and Germline Gene Therapy
Mechanism of In Vivo and Ex Vivo Gene Therapy
Differences between In Vivo and Ex Vivo Gene Therapy
Uses of gene therapy

Clinical gene transfer applications

Vaccine development

Production of transgenic animals

Treatment of cancer and AIDS

Gene discovery

Gene therapy

Enhancing the resistance of plant Genetically modified organism

Pharmacogenomics
Definition
“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 is the use of genetic information to guide the

choice of drug and dose on an individual basis.
Pharmacogenetics

Pharmacogenetics is referred to as the study of the effect

of genomic variations on drug response in terms of both
drug metabolism (pharmacokinetics) and drug action
(pharmacodynamics).

GOALS:
Maximum Drug efficacy
Minimum side effects
Predictive patient response
New drug development
Difference between Pharmacogenomics and Pharmacogenetics

Pharmacogenomics Pharmacogenetics
Use of genetic information to The study of genetic basis for
guide the choice of drug and dose variability in drug response.
on an individual basis.
Goals and outcomes achieved
1. Decreasd ADRs
2. Increased efficiency
3. Against trial and error method
4. High priority targets identified
5. Optimal prescribing
6. Major influence is of race
7. Major effect is of molecules interacting with
drug
Variations in Drug effects
THE FOUNDATION OF PHARMACOGENOMICS:

► Mutation:
Difference in the DNA code that occurs in less than 1% of population
▸ Often associated with rare diseases
E.g. 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
Single Nucleotide Polymorphism

▸ 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
Types of SNP
There are 3 billion nucleotides
Forming 25000-45000 genes
100000 Proteins formed
Types
1. Synonymous mutation: No change in
protein identity, structure and function
2.Nonsence mutations: Stop codon
3.Misscence mutation: Identity changed, may
change structure and function
POLYMORPHISMS

Variations in DNA sequences at locus

► 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
1. Pharmacokinetic Polymorphisms

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.
Cytochrome P450 enzymes

a) CYP2D6

*4 null allele. Example in Caucasian people

70-90% population with polymorphism ahow poor metabolism
❖ Metabolism of 20-25% of marketed drugs

Polymorphism best studied

Drugs: SSRI, TCA, beta blockers, antipsychotics

Codeine to Morphine metabolism
Tamoxifen metabolism

b) CYP2C19

More than 20 polymorphism reported

❖ Drugs: PPI, Mephenytoin,N-demethylation of TCA

amitryp, clomipramine, nortryp)

Proguanil to cycloguanil
c) CYP 2C9

Biotransformation of warfarin, phenytoin, fluvastatin, several NSAIDS,

Antidiabetics
Narrow therapeutic index drugs metabilzed
c) CYP3A4/5

Most abundant, most drugs metabilzed

Seen in human liver

Metabolism of more than 50% of drugs

20 variants identified

Eg: CYP3A4*16, CYP3A4*2, CYP3A4*7

Examples of genetical Polymorphism and drug response
2. Pharmacodynamic Variations

▸ Red cell enzyme defects

► G6PD- Sulfonamides, primaquine, dapsone,

nalidixic acid, nitrofurantoin, doxorubicin

► Serotonin reuptake transporters

► B2 receptors in Asthma
► Major role in cancer bcz only 10-20% efficacy.
E.g. Gefitinib in lung cancer
► Warfarin as P450 system and VKOR
► G6PD and X-linked disorders causing hemolysi
Advantages of Pharmacogenomics
Predict Patient Response to Drug
To Develop Customized Prescription
Achieve Better Efficacy and Safety
Minimize Toxicity and Adverse Effects
Improve Patient Compliance
Improve Drug Development Rationale
Accuracy in Dosage Form
Identification and Monitoring of certain
Diseases
Development of Personalized Medications
Disadvantages of Pharmacogenomics
1. Complexity of finding gene variations that affect
drug response.
 Study of Millions of SNPs (Single Nucleotide
Polymorphisms).
 Multi-Genetic Response.
 Specific Gene Identification.
 Cconfidentiality, privacy, use and storage of genetic
information
2. Educating healthcare providers & patients

3. Preparation of multiple pharmacogenomic

products
Pharmacogenetics in Practice

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 & H
with Abacavir

APOE & Tacrine in AD

Applications of Pharmacogenomics

1. Detection of Variation in CYP450 System

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

 Microassay is performed
1. Tissue samples taken e.g. Cancer cells
2. mRNA extracted
3. cDNA staining green and red according to
groups classified
4. Well of similar genes
5. cDNA is pipettees into welss
6. If genes bind each other yellow colour