PGx and Clinical Relevance

Question 1

Familial Hypercholesterolemia

Answer 1

autosomal co-dominant (wild type and mutation are expressed equally)
lipids deposit on eyelids and can spread throughout body and into heart and cause MI
Heterozygotes= 2-3 fold increase in LDL in blood
Homozygotes= 6-10 fold increase in LDL in blood

Question 2

FH Phenotypes

Answer 2

Class 1= no LDL receptors (null alleles)
Class 2= interferes with receptor going from ER to Golgi
Class 3= interferes with cell surface binding of receptor
Class 4= interferes with internalization of LDL - receptor complex
Class 5= interferes with receptor recycling

Question 3

Treatment of FH

Answer 3

• need early and aggressive LDL control
• developed statins once we understood the role of the receptors better
• statins inhibit HMG-CoA reductase –> produce less cholesterol –> in response, the liver up-regulates the LDL receptors to try to increase cholesterol level
• for homozygous null alleles= statins and diet do not work well –> need plasma LDL aphaeresis

Question 4

N-acetyltransferase 2 polymorphism (NAT2)

Answer 4

Phase II enzyme
Add a big molecule on the drug to make the drug more readily excreted by kidneys or liver
Detox of xenobiotics

Question 5

NAT2 genetics

Answer 5

autosomal dominant
Only 10% carry 2 normal functional alleles
To do phenotyping, administer a probe drug that you KNOW will be metabolized by the enzyme
In US, about half of our pop are slow acetylators

Question 6

NAT2 and carcinogens

Answer 6

NAT2 plays a role in inactivating carcinogens
Procarcinogens= by themselves, they do not cause cancer, but if they come into contact with activating enzymes, it becomes carcinogen
Increase in first square process and decrease in bottom square process –> increased risk of cancer
Slow acetylators= increased risk (usually a concurrent polymorphism in a Phase I enzyme)

Question 7

NAT2 and drug response

Answer 7

• Know that in slow acetylators= increased risk of toxicity/ drug-drug interactions
  
  • In rapid acetylators= decreased therapeutic efficacy

Question 8

G6PD deficiency

Answer 8

Most common enzyme deficiency worldwide
G6PD= important in how your body handles oxidative stress (In RBC’s this is the only pathway they have to deal with this)
can cause drug-induced hemolytic anemia
Distributed in countries closest to equator in the same countries that have highest incidence of malaria

Question 9

G6PD genetics

Answer 9

x-linked recessive (mostly males affected)

Question 10

Clinical relevance of G6PD deficiency and hemolytic anemia

Answer 10

most of the ones that are drug-induced are self-limiting

asymptomatic until triggered

Question 11

EGFR inhibitors in cancer therapy

Answer 11

• If you inhibit the receptor, you will inhibit proliferation
• Can inhibit receptor in 2 ways:
○ Monoclonal abx (“-umab”)= stops binding at receptor
○ Tyr kinase inhibitors= stops intracellular communication
Commonly used in non-small cell lung cancer

Question 12

Mutations in K-ras

Answer 12

constitutive active signaling
can also have mutation on EGFR receptor itself (makes it more sensitive to Tyr kinase inhibitors)
So mutation in K-ras makes TKI not as effective but mutation on EGFR receptor makes TKI still effective

Question 13

K-ras and colorectal cancer

Answer 13

• In patients with wild-type, adding the abx will help them
○ Might get better
• In pts with mutation, adding abx do not benefit much but still can have the toxicities
○ Might get worse
So genetic testing important in this case (especially since anti-EGFR antibodies are costly)

Question 14

When is PGx useful?

Answer 14

• When phenotype is relatively common
• When testing is available, accurate, and reliable
• When detection alters treatment and outcomes