Variability due to Genetic Differences

Question 1

What is the difference between pharmacogenomics and pharmacogenetics?

Answer 1

Pharmacogenomics: investigation of variations of DNA and RNA characteristics as related to drug response
Pharmacogenetics: the influence of variations in DNA sequence on drug response

Question 2

What are the two different types of variability?

Answer 2

Predictable: 50% of all. Genetic and environmental
Unpredicatble: 50% of all

Question 3

Which enzyme uses tacrolimus as its marker and which genes react differently?

Answer 3

CYP3A5
*1/1 genotype have two fold increase
3/3 are non expressors
80% caucasians but 25% africans

Question 4

What is the marker drug for N-acetyl-transferase acetylation and which ethnicities is low clearance found in?

Answer 4

Procainamide
white 50%
african 30%
asian 10%

Question 5

Why is UDP-Glucuronosyl-transferase glucuronidation important?

Answer 5

It eliminates active metabolite SN-38, but some patients get toxicity from this, predicted by the UGT1A1*28 gene
Marker drug is bilirubin

Question 6

How is alcohol affected by genetics?

Answer 6

Alcohol dehydrogenase increased activity with genotype ADH2*2 which forms increased acetaldehyde. 50-80% of Asians have this “asian flush”

Question 7

What do organic ion transporters, statins and SLCO1B1 have in common?

Answer 7

SLCO1B1 codes for an organic ion transporter which regulates the hepatic uptake of statins. With the mutation CC there is a 16 fold higher risk of myopathy

Question 8

Describe warfarin sensitivity and resistance

Answer 8

Gene VKORC1
Mutation causes hypersensitivity to warfarin 80% of asians
Reduced CYP4F2 activity leads to increased warfarin resistance 60% caucasians