Pharmacogenetics

Question 1

What do pharmacogenetics and pharmacogenomics address?

Answer 1

The question of the genetic basis for individual differences in the responses and adverse effects of drug treatment

Question 2

What are the four Ps of the personalized genome?

Answer 2

Predictive, preventive, personalized, participatory

Question 3

Define these terms:

1. monogenetic
2. polygenic
3. multi-factorial

Answer 3

1. The variation follows simple Mendelian Inheritance patterns
2. The variation results from multiple genes interacting with each other
3. The variation is caused through interactions with the environment

Question 4

What do these polymorphisms stand for?

1. SNP
2. Indels
3. CNVs

Answer 4

1. Single nucleotide polymorphisms
2. Insertions/deletions
3. Copy number variations: gene duplications and large deletions

Question 5

What are the two main considerations in pharmacogenetics?

Answer 5

Therapeutic failure and adverse effects

Question 6

Thiopurine S-methyltransferase (TPMT)

1. What kinds of drugs does it metabolize?
2. What happens if TPMT is too low?

Answer 6

1. Leukemia drugs, IBD and Crohn’s meds, RA and lupus medications
2. Unable to metabolize the drug –> effective level increases –> overdose at standard dose –> Hematopoietic toxicity

Question 7

Cytochrome P450 2D6 (CYP2D6)

1. What are some of its effects?
2. How can this be assessed without genome mapping?

Answer 7

1. Catalyze oxidation of organics, metoprolol metabolism, activation of codeine to morphine
2. “Probe drugs” : Measures the accumulation in the urine of the parent compound vs. its metabolites

**importnat in >40 drugs, including opioids

Question 8

Ultra-rapid metabolizer

Answer 8

Higher than normal enzyme activity; Usually due to gene duplication (CNV, occur with CYP2D6) - up to 13 copies
**No drug response at ordinary dosages

Question 9

Extensive metabolizer

Answer 9

Normal activity; Two copies of a normal gene

Question 10

Intermediate metabolizer

Answer 10

Half-normal enzyme activity; One copy of low activity gene

Question 11

Poor metabolizer

Answer 11

Little to no enzyme activity; Two copies of low activity gene
**High risk for adverse events, no response from certain prodrugs

Question 12

Warfarin

1. Why is dosing complicated?
2. What two main genes are implicated?

Answer 12

1. Pharmacokinetic and pharmacodynamics are SEPARATELY genetically determined (Polygenic inheritance)
2. CYP2C9 and VKORC1

Question 13

What gene variant causes people to be resistant to clopidogrel?

Answer 13

CYP2C19

Question 14

Vemurafenib

1. Use
2. Mechanism of action

Answer 14

1. Metastatic melanoma in patients with mutated BRAF

2. Inhibits V600E BRAF gene