Pharmacogenetics

Question 1

Define pharmacogenetics

Answer 1

A drug response related to a single or a few genes.

Question 2

Define pharmacogenomics

Answer 2

The study of variations of DNA and RNA characteristics as related to drug response.
- We can’t do this yet most of the time.

Question 3

Define SNPs

Answer 3

Single Nucleotide Polymorphisms

• Account for 90% of all human DNA polymorphisms.
• Synonymous
• Non-synonymous: matters

Question 4

Relevant pharmacogenetic examples:

Answer 4

• Aliskiren: ACE and REM
• ACE-Is: ACE
• ARBs: AGTR1
• Aldosterone antagonists: NR3C2

Question 5

Relevant polymorphisms

Answer 5

Drug metabolizing enzymes (CYPs)
- Ultra, rapid, normal, intermediate, and poor.

Drug transporters
- Increased, normal, decreased, and poor.

Human Leukocyte Antigen (HLA)

• Positive: carrier
• Negative: non-carrier

Question 6

Genotype nomenclature

Answer 6

For clinicians:
Gene*number/*number
- *1/*1 = normal
- *1/*2 = intermediate
- *2/*2 = poor

• That is generally speaking; can be gene-specific!
• Not all use star-number system at this point in time.

Question 7

The Three Rights

Answer 7

Right person.
- Someone that will actually benefit.

Right test.
- To gather the right information.

Right interpretation.
- How relevant and how to proceed.

Question 8

Methods of Variant Interrogation

Answer 8

Chip/Panel

• Look for a collection of predetermined variant SNPs
• May miss rare variants

Next Generation Sequencing

• Whole Genome Sequencing (WGS)
• Whole Exome Sequence (WES)
• Information overload.

Question 9

Phenotype can be affected by…

Answer 9

Drug interactions
In-vitro manipulations
Blood transfusions

Question 10

Abacavir

Answer 10

HLA-B*57:01

• Asian*
• Caucasian

0 - All good.
1 or 2 - change, unless already on it and okay.

Question 11

Allopurinol

Answer 11

HLA-B*58:01

• Asian*
• African American
• Middle Eastern

0 - All good.
1 or 2 - change, unless already on it and okay.

Question 12

CBZ/Ox/Phenytoin

Answer 12

HLA-A15:02
HLA-A31:01
- Asian

0 - All good.
1 or 2 - change, unless already on it and okay.

Question 13

2D6 and Codeine

Answer 13

2D6 polymorphisms that with increased activity lead to higher rates of conversion to morphine - dangerous in children.

• M6G: analgesia
• M3G: SE’s

Question 14

2D6 and Tramadol

Answer 14

2D6 polymorphisms with increased activity lead to higher rates of conversion to O-desmethyl tramadol
- M1: analgesia

Question 15

2D6 and Oxycodone

Answer 15

to Oxymorphone

Question 16

2D6 and Hydrocodone

Answer 16

to Hydromorphone

Question 17

Ethnic variability in 2D6 phenotypes

Answer 17

Ultra-rapid most common in Africans/Ethiopian and African American

Question 18

CPIC guidelines for 2D6 and Codeine

Answer 18

Ultrarapid metabolizers

• Avoid Codeine
• Try morphine or non-opiods.

Extensive (normal) - okay
Intermediate - okay

Poor metabolizer

• Avoid Codeine
• Try morphine or non-opioids.

Question 19

2C19 and Clopidogrel

Answer 19

Do not use in poor metabolizers b/c required for activation.

Question 20

Pertinent 2C19 medications:

Answer 20

Clopidogrel
PPI’s
Some antidepressants
Voriconazole

Question 21

CYP2C19 Polymorphisms

Answer 21

• 2 - loss of function
• 1/3 asians
• 2/3 oceanians
• 3 - loss of function
• asians
• 17 - gain function
• caucasians
• africans

Question 22

CPIC guidelines for 2C19 and Clopidogrel

Answer 22

Use something else if intermediate or poor metabolizer.

Question 23

Enzymes relevant to Warfarin

Answer 23

CYP 2C9

VKORC1

Question 24

2C9 and Warfarin

Answer 24

Required for inactivation of S-Warfarin
Common poly: *2 and *3
Effects: reduced metabolism
Prevalence: mostly caucasian
Clinical significance: reduce initial dose

Question 25

KVORC1 and Warfarin

Answer 25

Reduces VitK to active form
Common poly: 1639G (more) and A(rs9923231)
Effects: Alters VKORC1 transcription binding site, leading to lower protein expression
Prevalence: Asian > Caucasian > AA
Clinical Significance: reduce initial dose

Question 26

Role of the Pharmacist

Answer 26

Recommend
- pharmacogenomic testing

Design
- patient-specific regimen

Educate
- other healthcare professionals

Communicate

• to team
• on patient’s health record