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Pharmacogenetics Midterm > PGx and Clinical Relevance > Flashcards

Flashcards in PGx and Clinical Relevance Deck (14):

Familial Hypercholesterolemia

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


FH Phenotypes

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


Treatment of FH

*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


N-acetyltransferase 2 polymorphism (NAT2)

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


NAT2 genetics

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


NAT2 and carcinogens

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)


NAT2 and drug response

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


G6PD deficiency

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


G6PD genetics

x-linked recessive (mostly males affected)


Clinical relevance of G6PD deficiency and hemolytic anemia

most of the ones that are drug-induced are self-limiting
asymptomatic until triggered


EGFR inhibitors in cancer therapy

• 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


Mutations in K-ras

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


K-ras and colorectal cancer

• 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)


When is PGx useful?

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