Pharmacogenetics

Question 1

Pharmacogenetics

Answer 1

Evaluates how an individual’s genetic makeup corresponds to their response to a particular medication
Looks at specific allele differences within a single gene

Question 2

Pharmacogenomics

Answer 2

Combines pharmacogenetics with genomic studies
Uses large groups of patients to evaluate how candidate drugs interact with a range of genes and their protein products
Examines the entire genome for allele differences
No target known
Identified SNP may have direct link to phenotyp
Require large genome wide association studies

Question 3

Goals for personalized medicine

Answer 3

Identify genetic differences between people that affect drug response
Develop genetic tests that predict an individual’s response to a drug
Tailor medical treatments to the individual

Question 4

Ultra drug metabolizers vs Poor drug metabolizers for

1. Drugs
2. Pro-drugs

Answer 4

1. UM: inactivation of the drug, PM: toxic doses

2. UM: active form/toxic doses, PM: little conversion/ineffective

Question 5

3 main consequences of genetic polymorphisms

Answer 5

1. None (outside of coding and regulatory regions, synonymous substitution, no impact on function of protein)
2. Decrease or loss of function of the encoded protein
3. Increase in function of the encoded protein

Question 6

4 results of a decrease in function mutation

Answer 6

Less enzyme may be produced (decreased regulation)
Enzyme may not be complete (stop codon insertion)
Enzyme may not be as stable
Less binding affinity to substrate

Question 7

3 results of a increase in function mutation

Answer 7

More production (regulation or genomic copies)
More stable
More binding affinity

Question 8

Tuberculosis

Answer 8

An infectious disease caused by Mycobacterium tuberculosis
Typically attacks the lungs, but can affect other parts of the body
Airborne disease

Question 9

What drug is used to treat tuberculosis?

Answer 9

Isoniazid

Question 10

Isoniazid

Answer 10

Used to treat TB
Metabolized in the liver via acetylation and then cleared from the body
High incidence of peripheral neuropathy caused by the drug reaching toxic levels

Question 11

What enzyme acetylates isoniazid?

Answer 11

N-Acetyl-Transferase

NAT2

Question 12

NAT2 gene

Answer 12

Has several alleles which cause variation in the rate of acetylation of various drugs including isoniazid

Question 13

NAT2

1. Rapid acetylator
2. Slow acetylator

Answer 13

1. Wild type, dominant allele

2. Various amino acid substitution in NAT2 lead to reduced efficiency of gene, recessive

Question 14

Thiopurines are used to treat…

Answer 14

Acute lymphoblastic leukemia
Inflammatory bowel disease
Prevent organ rejection after transplantation
Other autoimmune diseases

Question 15

Thiopurine methyltransferase (TPMT)

Answer 15

An enzyme that allows methylation of thiopurines
Thiopurines are converted into thioguanine nucleotides and get inserted into DNA bases and can have toxic effects within the cell at high levels
Reduced TPMT activity can lead to fatal toxicity

Question 16

TMPT Clinical relevance

Answer 16

Patients with 2 nonfunctional variant alleles are given 6-10% of the standard dose of thiopurines
Heterozygous patients can be started on full dose but must be closely monitored to avoid toxicity

Question 17

Consequences if you have no CYP2D6 enzymes

Answer 17

Poor drug metabolizers
Too slow drug metabolism
Too high drug levels at ordinary dose
High risk for adverse drug results
No response from certain prodrugs

Question 18

Consequences if you have CYP2D6 gene duplications

Answer 18

Ultra rapid drug metabolizers

No drug response at ordinary dosage

Question 19

Nortriptyline

Answer 19

Used to treat major depression
Inhibits the reuptake of norepinephrine and to a lesser extent serotonin
Has a narrow therapeutic index (therapeutic dose is close to toxic dose)

Question 20

Side effects of nortriptyline in a poor drug metabolizer

Answer 20

Mild: drowsiness, dry mouth, nausea, headache
Serious: seizures, cardiac rhythm disturbances

Question 21

Tamoxifen

Answer 21

Used for the treatment of ER+ breast cancer
Prodrug
Metabolized by CYP2D6 to its active metabolites 4-hydroxytamoxifen and endoxifen

Question 22

What is the result in function for the following CYP2D6 allele frequencies?

1. *2xN
2. *10
3. *17
4. *4
5. *5

Answer 22

1. increased function
2. decreased function
3. decreased function
4. no function
5. no function

Question 23

Plavix

Answer 23

Used to treat blood clots
Prodrug is metabolized by CYP2C19 to active form
Some alleles result in a poor metabolizer resulting in an inactive drug

Question 24

3 requirements for pharmacogenetics to work

Answer 24

Knowledge of target genes ahead of time
Direct link between SNP and phenotype
Require fairly small sample sizes to identify

Question 25

How to detect SNPs

Answer 25

Isolate DNA
Digest DNA into ‘bite sizes’ chunks
Label DNA with a fluorescent probe
Hybridize onto a matrix containing an array of oligonucleotides representing known SNPs
Detect signal for each SNP spot on the array

Question 26

Treatment for Hep C

Answer 26

Interferon combined with ribavirin