Clinical Relevance

Question 1

What can be the effects of a genetic mutation?

Answer 1

Knockout/reduce/enhance activity

Increase/decrease disease risk or severity

Question 2

3 important clinically relevant things?

Answer 2

Role of the enzyme in drug kinetics/response
Prevalence of the mutation
Narrow therapeutic index drugs

Question 3

FH is the number one cause of?

Answer 3

Monogenic hypercholesterolemia (chromosome 19 and autosomal co-dominant)

Question 4

FH phenotypes

Answer 4

Some code for 0 receptors
Some mess with transport
Some mess with binding

Question 5

Normal pathophysiology before FH

Answer 5

LDL receptors is bound by LDL and it gets internalized and made into other things and the levels decrease

Question 6

FH pathophysiology

Answer 6

Levels stay high because there is a problem with the receptor

Question 7

Pathogenesis of atherosclerosis

Answer 7

Hypercholesterolemia –> atherosclerosis –> CAD

Question 8

How do statins work?

Answer 8

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

Question 9

What is the FH patient has homozygous null alleles

Answer 9

Statins and diet do not work well

Question 10

NAT2 importance

Answer 10

Susceptibile to cancer

Phase II enzyme

Question 11

What does a phase II enzyme do?

Answer 11

Conjugates to a larger polar molecule to help get rid of it

Question 12

NAT2 Genetics

Answer 12

All are SNPs or SNP combinations
Autosomal dominant (10% for wildtype)

Question 13

CYP3A4*1 is

Answer 13

Wildtype

Question 14

CYP3A4*2

Answer 14

Variant

Question 15

How do you categorize people as fast or slow acetylators?

Answer 15

Give them a probe and then you measure the concentration in the blood

Question 16

Fast acetylators =

Answer 16

Normal acetylators

Question 17

In the US how many people are slow acetylators?

Answer 17

50%

Question 18

NAT normal does what?

Answer 18

Inactivates metabolites from the environment (cig smoke)

Slow acetylators cannot do this as well and so this can lead to cancer

Question 19

What combination makes getting cancer more likely?

Answer 19

Slow acetylator
Concurrent phase I enzymes polymorph
Significant gene-gene or gene-environment interaction

Question 20

If you are a poor acetylator, you are?

Answer 20

At an increased risk for disease

Question 21

If they are slow or rapid acetylators, what happens?

Answer 21

Slow: higher risk of side effects
Rapid: decreased therapeutic effect

Question 22

Drug toxicity leads to?

Answer 22

Drug induced anemia

Question 23

Drug efficacy leads to?

Answer 23

Colorectal cancer

Question 24

RBC are highly dependent on?

Answer 24

G6PD pathway of getting rid of oxidants

Question 25

Drug induced oxidative stress is caused by?

Answer 25

Primaquin
Salicylates
Sulfonamides
Nitrofurans
Vitamin K derivatives

Question 26

G6PD Deficiency is?

Answer 26

X linked recessive inheritance

Non-frameshift triplet deletion

Question 27

G6PD deficiency clinically is?

Answer 27

Asymptomatic until triggered (drugs, fava beans, infections)

Question 28

G6PD deficiency manifests as?

Answer 28

Jaundice, pallor, dark urine, fatigue

Question 29

EGFR in cancer therapy

Answer 29

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

Question 30

Kras in Colorectal Cancer

Answer 30

Wildtype benefit from addition of anti-EGFR but mutants do not
These drugs are expensive too

Question 31

When is pharmacogenetic useful?

Answer 31

Detecting alternate treatment and outcomes with narrow therapeutic window, serious toxicity or lack of activity or marginal efficacy