MODULE 6- Pharmacogenomics I

Question 1

Variation among patients in their responses to
medication is noted
Due to:

Answer 1

o Environmental factors
– Drug-drug interactions
– Co-morbid disease
– Age, sex, diet
o Genetic factors

Question 2

The Goal of Pharmacogenomics

Answer 2

• To identify genetic differences among patients that
influence treatment response
• This is essential in 3 main areas:
– 1. Efficacy
– 2. Safety
– 3. Optimum dose

Question 3

1. efficacy

Answer 3

• Drug resistance or non-response is a serious
clinical issue
– E.g. 30% of patients with epilepsy and 30-50% of
patients with schizophrenia do not respond to any
currently available drug treatment
• Studies that elucidate the genetic basis of
treatment failure facilitate the development of new
compounds

Question 4

2. safety

Answer 4

• Drug treatment is frequently associated with adverse
drug reactions (ADRs)
– mild to fatal
• Estimated 5-13% of hospital admissions are due to
ADRs (first world)
• Many medications fail clinical trials or need to be
withdrawn from the market due to ADRs
• E.g. severe ADR has led to the withdrawal of drugs including
astemizole (allergy medication), grepafloxacin (an antibiotic), sertindole
(an antipsychotic)

Question 5

3. dose

Answer 5

• Many drugs have a narrow therapeutic range
– too high → toxicity and dose-related ADR
– too low, → not effective
– e.g. warfarin
• Different patients can require dramatically
different doses
– e.g. epileptic, cancer, and psychiatric drugs
– dose titration can take months

Question 6

Pharmacogenomics aims to

Answer 6

– develop rational means to optimize drug therapy, with respect
to the patients’ genotype
– ensure maximum efficacy with minimal adverse effects
So: two people with the same diagnosis might receive
different therapies or drug dosages

Question 7

pharmacogenomics

Answer 7

The study of the interaction of an individual’s genetic
makeup and response to a drug

studying the effect many
variants across the genome

Question 8

pharmacogenetics

Answer 8

studying the effect of one

a variant in one gene

Question 9

What is the genetic study approach?

Answer 9

1. take a group of patients, non-responders,responders, toxic responders
2. Look at genotype of each group
3. Which gene variants are specific to each group?
4. Associated variants can be used as a diagnostic tool to
   predict a person’s drug response

Question 10

Drug response is polygenic and is influenced

by environmental factors

Answer 10

drug response is a multifactorial trait

Question 11

what is haplotype

Answer 11

• In genetic studies, groups of
variants are often found to be
associated with a particular trait
– Haploid – cell having one set of
chromosomes
– Genotype – genetic make-up
• ‘Haplotype’: describes a group or
cluster of variants inherited
together from one parent on one
chromosome
– inherited together because they are
physically close to each other on the
same chromosome

Question 12

ADME genes

Answer 12

A – Absorption
• D – Distribution
• M – Metabolism
• E – Excretion
• Genes that are associated with drug metabolism
– metabolism enzymes
– transporters

Question 13

ADME genes currently described

• 32 core genes plus 340 extended genes

Answer 13

true

Question 14

A higher diversity has been observed in some functionally important ADME genes in African
Americans as compared to Europeans (Li et al 2014)

Answer 14

– “drug response heterogeneity between populations”
– significant genetic differences in the ADME genes between different populations could
lead to therapeutic failure, or adverse drug responses

Question 15

Inconsistent patient responses to

drug therapies

Answer 15

Poor metabolisers:
– build up of drug in liver
• can be toxic
– lack of efficacy
→give less drug

• Ultra-rapid metabolisers:
– drug cleared too quickly in
liver
– lack of efficacy
→give more drug

Question 16

Genetics explains inconsistent

response phenotypes

Answer 16

Poor metaboliser:
– two non-functional alleles
• Intermediate metaboliser:
– one functional allele and
one non-functional allele
– OR two partially functional
alleles
• Extensive metaboliser:
– two functional alleles
• Ultra-rapid metaboliser:
– more than one increased
functional allele

Question 17

Drug Metabolising Enzymes

Answer 17

• > 30 families
• e.g. cytochrome P450 (CYP450) superfamily
– Metabolise approx 60% of prescribed drugs
– Expressed primarily in liver
– 57 genes known to date
– 3 families: CYP1, CYP2, CYP3

Question 18

Drug Metabolising Enzymes – CYP2

Answer 18

• Most polymorphic of all CYP450 enzymes
• 20 to 30% of all drugs metabolised
• subfamilies A – E
• genes are described e.g. CYP2D6, CYP2C8
• Variants (alleles) are described e.g. CYP2C91,
CYP2C92, CYP2C9*3

Question 19

Types of genetic variants

Answer 19

Metabolic pathways are affected by a wide
range of types of DNA variants including
– single nucleotide polymorphisms (SNPs)
– mutations in the regulatory elements of genes
– variable number of tandem repeats (VNTRs)
– variations in gene copy number (gene deletions or
duplications)

Question 20

examples

Answer 20

refer to the document

Question 21

The aim of studying pharmacogenomics

Answer 21

To inform:
Personalised Medicine /
Precision Medicine

Question 22

Definition of Precision Medicine

Answer 22

Medical care designed to optimize efficiency or therapeutic
benefit for particular individual / groups of patients, especially
by using genetic or molecular profiling

Question 23

Serious considerations

Answer 23

Availability of technology

- Cost

Question 24

Precision Public Health

vs Precision Personalised Medicine

Answer 24

New concept of ‘Precision Public Health’
• Health decisions based on populations and
communities as opposed to individuals
• More cost-effective approach for developing countries
In Botswana, efavirenz is no longer a first line ARV and changes
are being considered for recommended first line treatments in
Zimbabwe and South Africa

Question 25

Different African ethnicities each need to evaluate the
frequencies (even complete absence?) of various
polymorphisms involved in the pharmacogenomics of a
particular drug

Answer 25

true

Question 26

Practical hurdles to implementing

pharmacogenomic testing at present

Answer 26

• Complexity of finding gene variations that affect drug
response
• Some polymorphisms do not show associations in
different ethnic groups
• Limited drug alternatives
• Disincentives for drug companies to make multiple
pharmacogenomic products
Educating healthcare providers

Question 27

take-home message

Answer 27

• Necessary to set boundaries in the expectations of the applications of
pharmacogenomics to clinical medicine
• Health-care professionals need to become educated in the interpretation
of genetic data (what genetic testing can and cannot tell you..)
• Clear differences exist between African, Asian and Caucasian population
structure demonstrating the need for population-specific preclinical and
clinical studies and trials
• Precision health (as opposed to precision medicine) is important to
consider for a health care system in a developing country