Pharmacogenetics

Question 1

What is stratified medicine?

Answer 1

Selecting therapies for groups of people based of shared biological characteristics.

Question 2

What kind of genetic variations may affect drugs?

Answer 2

• Gene amplification
• Promotor polymorphisms
• Translocations
• Deletions/insertions
• SNPs

Question 3

What sort of drug properties may be affected by genetic variation?

Answer 3

Absorption
Activation
Altered target 
Catabolism (breakdown)
Excretion/elimination

Question 4

What are the consequences of the impact of genetic variation on the drugs?

Answer 4

Inactive drug - poor/no response
Over-active drug - excess toxicities
Financial costs to the health service

Question 5

What is Azathioprine?

Answer 5

Immusuppressant - used in organ transplantation, Crohns, cancers etc

Question 6

How does Azathioprine work?

Answer 6

Inhibits DNA synthesis

Question 7

What is the relevance of thiopurine methyltransferase (TPMT)?

Answer 7

TPMT inactivates azathioprine. Some populations have polymorphisms which adversely affect its enzyme activity. These populations have higher serum levels of azathioprine and experience worse side effects.

Question 8

What is N-Acetyltransferase?

Answer 8

A group of liver enzymes inactivating drugs by acetylation. There are ‘fast’ and ‘slow’ acetylators due to SNPs.

Question 9

What effect do SNPs for N-Acetyltransferase have on the metabolism of isoniazid (TB drug)?

Answer 9

Slow acetylators are at increased risk of toxicity (neuritis and liver toxicity).

Question 10

What is the relevance of the BCHE gene to succinylcholine?

Answer 10

Homozygotes have reduced butyrylcholinesterase activity. Effects may last for an hour or more and risk of death if artificial ventilation is not continued.

Question 11

What is the mechanism for aminoglycoside-associated hearing loss?

Answer 11

Mitochondrial MT-RNR1 gene encodes mitochondrial 12s rRNA

G>A mutation at nucleotide position 1555 causes non-syndromic hearing loss (at later ages)

Mutation changes the structure of the rRNA to resemble E-coli 16S rRNA

Aminoglycosides more likely to bind to patients rRNA → increased risk of hearing loss at younger age

Maternal inheritance

Accounts for 30% of tendency to aminoglycoside ototoxicity

Question 12

Which gene explains 50% of the genetic variability to warfarin?

Answer 12

CYP2C9

Question 13

What is transtuzumab?

Answer 13

Herceptin - monoclonal antibody to HER2 receptor. 20% of breast cancers over-express HER2 and herceptin is a very good treatment in this 20%.

Question 14

What is vemurafenib?

Answer 14

BRAF enzyme inhibitor. BRAF is over-expressed in 50% of melanoma?