Pharmacogenomics

Question 1

List 3 values of pharmacogenomics

Answer 1

1) Optimized dose
2) Optimized drug choice
3) Optimizing drug therapy -> right drug to the right patient

Question 2

List 8 types of gene variants

Answer 2

1) Single Nucleotide polymorphism
2) Insertion
3) Deletion
4) Copy number variation
5) Tandem duplication
6) Interspersed duplication
7) Translocation
8) Inversion

Question 3

What are same alleles also known as?

Answer 3

Homozygous

Question 4

What are different alleles also known as?

Answer 4

Heterozygous

Question 5

What is an allele?

Answer 5

Version of a gene

Question 6

What is a haplotype?

Answer 6

A set of DNA variations inherited together on the same allele

Question 7

What is a genotype?

Answer 7

A combination of different alleles at a specific location in DNA

Question 8

What are phenotypes?

Answer 8

Observable traits
E.g. normal metabolizer, poor metabolizer, skin colour, hair colour

Question 9

*1 alleles are usually known as?

Answer 9

Wild type/ absence of variant tested

Question 10

How is the genotype for HLA usually presented?

Answer 10

Positive/negative- considered at risk even with 1 copy

Question 11

HLA mostly predicts for?

Answer 11

Hypersensitivity risk

Question 12

List 3 main enzymes where activity score is usually used to predict the phenotype for?

Answer 12

CYP2C9, CYP2D6, DPYD

Question 13

Based on the activity score, what does the score 2.0 stand for?

Answer 13

Normal (Extensive) Metabolizer

Question 14

Based on the activity score, what does the score 3.0 stand for?

Answer 14

Ultrarapid metabolizer

Question 15

State whether the following is true or false: phenotype is predicted based on genotype

Answer 15

True

Question 16

State whether the following is true or false: phenotype is affected by other clinical factors e.g. organ function, drug interaction

Answer 16

True

Question 17

List 4 main resources for pharmacogenomics

Answer 17

1) CPIC- American Clinical guidelines
2) DPWG - dutch clinical guidelines
3) PharmGKB - one stop database that curates current PGx knowledge
4) Sequence2script

Question 18

What does genotyping assay do? List down 1 disadvantage of genotyping assays

Answer 18

Tests for specific variants

Disadvantage: will miss variants that weren’t included in the test

Question 19

What does sequencing assay do? List down 2 disadvantages of this assay

Answer 19

Identifies all variants within the regions tested

Disadvantages:
1) Expensive
2) Turn-around-time is typically longer

Question 20

List down 2 caveats to the use of pharmacogenomics in practice

Answer 20

1) *1 represents the absence of variants covered by a genotyping panel

2) Behavioural, social and environmental factors may affect drug response and contribute phenoconversion

Question 21

How does PGx optimise pharmacotherapy?

A) helps with choice of drug
B) helps with dosing
c) Both A & B

Answer 21

C) Both A & B

Question 22

Which of the following is NOT considered a type of genetic variation?

A) Single nucleotide polymorphism
B) Copy number variation
C) Phenoconversion
D) Insertion

Answer 22

C) Phenoconversion

Question 23

Which of the following is a potential genotype reported for HLA-B* 15:02?

A) Rapid metabolizer
B) 2/3
C) A/A
D) Positive

Answer 23

Positive

Question 24

Which part should I focus on when interpreting a PGx report?

A) Genotype
B) Phenotype

Answer 24

B) Phenotype

Question 25

Which of the following is NOT a resource for translating genotype/phenotype for therapeutic recommendations? A) CPIC B) PharmVar C) DPWG D) PharmGKB

Answer 25

B) PharmVar

Question 26

Which of the following is a more accurate depiction of *1 in a genotyping assay? A) wild type allele B) Absence of variants covered by the assay

Answer 26

B) Absence of variants covered by the assay

Question 27

Which of the following could cause phenoconversion i.e. mismatch between genotype and predicted phenotype? A) Organ failure B) Diet C) Drug drug interactions D) All of the above

Answer 27

D) all of the above

Question 28

List the substrates of CYP2B6 (3)

Answer 28

1) Tramadol 2) Vortioxetine 3) Sertraline

Question 29

List the substrates for CYP2C9 (3)

Answer 29

1) Clopidogrel 2) Vortioxetine 3) Sertraline

Question 30

Which drug is an example of a weak inhibitor of CYP2B6

Answer 30

Clopidogrel

Question 31

Which drug is a prodrug that is converted to an active metabolite by CYP2C19?

Answer 31

Clopidogrel

Question 32

List the substrates for CYP2C19 (5)

Answer 32

1) Clopidogrel -> converted to active metabolite 2) Omeprazole 3) Escitalopram 4) Vortioxetine 5) Sertraline

Question 33

Give an example of a drug that is a moderate inhibitor of CYP2C19

Answer 33

Omeprazole

Question 34

Which drug is converted to an active metabolite with a much higher activity by CYP2D6?

Answer 34

Tramadol -> converted to active metabolite that has 200x more activity

Question 35

List the substrates of CYP2D6 (8)

Answer 35

1) Tramadol -> active metabolite 2) Escitalopram 3) Venlafaxine (major) 4) Amitriptyline 5) Fluvoxamine 6) Paroxetine (major) 7) Vortioxetine (major) 8) Sertraline

Question 36

List 3 examples of weak inhibitors of CYP2D6

Answer 36

1) Escitalopram 2) Venlafaxine 3) Sertraline

Question 37

What is a drug that is a strong inhibitor of CYP2D6?

Answer 37

Paroxetine

Question 38

List substrates for CYP3A4 (7)

Answer 38

1) Clopidogrel 2) Omeprazole 3) Tramadol 4) Escitalopram 5) Atorvastatin 6) Vortioxetine 7) Sertraline

Question 39

Omeprazole is a weak inhibitor of which enzymes?

Answer 39

CYP3A4, CYP3A5

Question 40

List the substrates for CYP3A5 (5)

Answer 40

1) Clopidogrel 2) Omeprazole 3) Tramadol 4) Escitalopram 5) Atorvastatin

Question 41

Which gene affects the drug response of rosuvastatin?

Answer 41

ABCG2 gene

Question 42

Which gene testing is mandated by HSA/MOH and for which drug?

Answer 42

HLA-B*15:02 For carbamazepine to avoid SJS/TENs

Question 43

Which gene is also associated with hypersensitivity in carbamazepine that is not mandated in SG?

Answer 43

HLA-B*31:01; more prevalent in European and Japanese population

Question 44

What gene has been reported to be related to cause adverse liver reactions, and in which drug?

Answer 44

HLA-B*57:01 Flucloxacillin FYI: associated with hypersensitivity in abacavir

Question 45

Which gene is associated with SCAR in allopurinol?

Answer 45

HLA-B*58:01

Question 46

Which gene is known to affect drug response to statins?

Answer 46

SLCO1B1; Simvastatin (most affected), atorvastatin

Question 47

If a patient is found to be a CYP2D6 ultra-rapid metabolizer, list 3 drugs that will be affected, and the respective recommended changes to be made for these drugs.

Answer 47

1) Paroxetine: consider alternative therapy 2) Venlafaxine: increase dose 3) Vortioxetine: consider alternative therapy/ increase dose

Question 48

If a patient is found to be a CYP2D6 intermediate metabolizer, list 1 drugs that will be affected, and the respective recommended changes to be made for the drug.

Answer 48

1) Paroxetine: decrease dose/slower titration

Question 49

If a patient is found to be a CYP2D6 poor metabolizer, list 4 drugs that will be affected, and the respective recommended changes to be made for these drugs.

Answer 49

1) Paroxetine: decrease dose/slower titration 2) Fluvoxamine: consider alternative OR decrease dose/slower titration 3) Venlafaxine: consider alternative OR decrease dose/slower titration 4) Vortioxetine: consider alternative OR decrease dose/slower titration

Question 50

If a patient is found to be a CYP2C19 ultra-rapid metabolizer, list 1 drug that will be affected, and the respective recommended changes to be made for the drug

Answer 50

1) Escitalopram: consider alternative/ increase dose

Question 51

If a patient is found to be a CYP2C19 rapid metabolizer, list 1 drug that will be affected, and the respective recommended changes to be made for the drug

Answer 51

1) Escitalopram: consider alternative/ increase dose

Question 52

If a patient is found to be a CYP2C19 intermediate metabolizer, list 2 drugs that will be affected, and the respective recommended changes to be made for the drugs

Answer 52

1) Escitalopram: decrease dose/ slower titration 2) Sertraline: decrease dose/ slower titration

Question 53

If a patient is found to be a CYP2C19 poor metabolizer, list 2 drugs that will be affected, and the respective recommended changes to be made for the drugs

Answer 53

1) Escitalopram: consider alternative OR decrease dose/slower titration 2) Sertraline: consider alternative OR decrease dose/slower titration

Question 54

List 2 factors that supports the decision to conduct HLA-B*58:01 gene testing for allopurinol

Answer 54

1) Renal impairment 2) Old age