Clinical Relevance Flashcards
What can be the effects of a genetic mutation?
Knockout/reduce/enhance activity
Increase/decrease disease risk or severity
3 important clinically relevant things?
Role of the enzyme in drug kinetics/response
Prevalence of the mutation
Narrow therapeutic index drugs
FH is the number one cause of?
Monogenic hypercholesterolemia (chromosome 19 and autosomal co-dominant)
FH phenotypes
Some code for 0 receptors
Some mess with transport
Some mess with binding
Normal pathophysiology before FH
LDL receptors is bound by LDL and it gets internalized and made into other things and the levels decrease
FH pathophysiology
Levels stay high because there is a problem with the receptor
Pathogenesis of atherosclerosis
Hypercholesterolemia –> atherosclerosis –> CAD
How do statins work?
HMG-CoA Reducatase inhibitors
Prevent cholesterol formation and so hepatocytes increase the receptor on the cell so that it will end up taking up more LDL and getting rid of it
What is the FH patient has homozygous null alleles
Statins and diet do not work well
NAT2 importance
Susceptibile to cancer
Phase II enzyme
What does a phase II enzyme do?
Conjugates to a larger polar molecule to help get rid of it
NAT2 Genetics
All are SNPs or SNP combinations Autosomal dominant (10% for wildtype)
CYP3A4*1 is
Wildtype
CYP3A4*2
Variant
How do you categorize people as fast or slow acetylators?
Give them a probe and then you measure the concentration in the blood
Fast acetylators =
Normal acetylators
In the US how many people are slow acetylators?
50%
NAT normal does what?
Inactivates metabolites from the environment (cig smoke)
Slow acetylators cannot do this as well and so this can lead to cancer
What combination makes getting cancer more likely?
Slow acetylator
Concurrent phase I enzymes polymorph
Significant gene-gene or gene-environment interaction
If you are a poor acetylator, you are?
At an increased risk for disease
If they are slow or rapid acetylators, what happens?
Slow: higher risk of side effects
Rapid: decreased therapeutic effect
Drug toxicity leads to?
Drug induced anemia
Drug efficacy leads to?
Colorectal cancer
RBC are highly dependent on?
G6PD pathway of getting rid of oxidants
Drug induced oxidative stress is caused by?
Primaquin Salicylates Sulfonamides Nitrofurans Vitamin K derivatives
G6PD Deficiency is?
X linked recessive inheritance
Non-frameshift triplet deletion
G6PD deficiency clinically is?
Asymptomatic until triggered (drugs, fava beans, infections)
G6PD deficiency manifests as?
Jaundice, pallor, dark urine, fatigue
EGFR in cancer therapy
If EGFR is activated there is cell proliferation so target this to turn off proliferation of cancer cells
Unless there is a mutation in RAS and then it is always on and always proliferating
Kras in Colorectal Cancer
Wildtype benefit from addition of anti-EGFR but mutants do not
These drugs are expensive too
When is pharmacogenetic useful?
Detecting alternate treatment and outcomes with narrow therapeutic window, serious toxicity or lack of activity or marginal efficacy
