Cardiovascular Disease

Question 1

Active efflux of clopidogrel is thru what?

Answer 1

ABCB1

Question 2

Degradation of clopidogrel is by what?

Answer 2

Intestinal esterases

Question 3

How is clopidogrel activated?

Answer 3

Activated to active metabolite via 2 steps

1. CYP2C19
2. Possibly PON1

Question 4

What is the target site of clopidogrel?

Answer 4

P2Y12, located on platelets

Question 5

What is the role of CYP2C19 in the metabolic activation of clopidogrel?

Answer 5

It occurs in both steps of metabolic activation

Question 6

What are the genetic variations of CYP2C19?

Answer 6

Loss of function alleles (*2 and *3)

Gain of function allele (*17)

Question 7

In what ancestry flow is there an increase of both intermediate CYP2C19 alleles and poor metabolizers?

Answer 7

Caucasian to AA to Asian

Question 8

CYP2C19*3 is exclusively in what population?

Answer 8

Asian

Question 9

What have studies show about the significance of CYP2C19 LOF and GOF alleles?

Answer 9

Increased odds of cardiac events and stent thrombosis

*17 has not shown any regard to efficacy, just increased bleeding risk

Question 10

PON1 has been shown to be a critical enzyme in activating clopidogrel, what have follow-up studies show?

Answer 10

Failed to replicate any impact on outcome or surrogate clinical markers

Question 11

What are some factors that can contribute to responses to clopidogrel?

Answer 11

1. Diet
2. ABCB1/CYP2C19 polymorphism and PON1
3. Smoking
4. Drug-drug interactions (notably PPIs)
5. Intrinsic variation in platelet function

Question 12

For poor metabolizers of CYP2C19, what must FDA require?

Answer 12

Black box warning regarding diminished effect of clopidogrel

Question 13

For intermediate metabolizers of CYP2C19, what must FDA require?

Answer 13

They dont address it like poor metabolizers

Question 14

Why should known CYP2C19 poor and intermediate metabolizers switch from clopidogrel to prasugrel/ticagrelor?

Answer 14

Likelihood of Tx failure

Question 15

How does warfarin work?

Answer 15

Works thru negative effect on Vit. K epoxide reductase which decreases production of clotting factors (2,7,9,10)

Question 16

(R or S)-warfarin is more potent

Answer 16

S

Question 17

(R or S)-warfarin is metabolized via CYP2C9

Answer 17

S

Question 18

What are the key genetic impacts on warfarin use and which one is race exclusive?

Answer 18

1. CYP2C9
2. CYP4F2
3. VKORC1 (25%)
4. CALU**
5. Age, body size, RX (15-20%)

**AA only (5.7%)

Question 19

What does CYP2C9*2 and *3 do w/ warfarin?

Answer 19

Decrease clearance by 40 to 75%

Question 20

What is the most and least common CYP2C9 allele?

Answer 20

Most common (69%) = Wildtype

Least common (6%) = Homo LOF

Question 21

Which genotype decreases warfarin clearance by 40 to 75%?

Answer 21

CYP2C9*2 and *3

Question 22

What are the VKORC1 haplotypes?

Answer 22

Group A and B

Question 23

Haplotype Group A is associated w/ (lower/higher) dosing of warfarin to achieve INR

Answer 23

lower

Question 24

Haplotype Group A includes what kind of haplotypes?

Answer 24

H1 and H2

Question 25

Haplotype Group B is associated with (lower/higher) dosing of warfarin to achieve INR

Answer 25

higher

Question 26

Haplotype Group B includes what kind of haplotypes?

Answer 26

H2, H8, and H9

Question 27

What population is CYP4F2*3/*3 allele found in? What is its significance?

Answer 27

Caucasians, rare in AA Decrease risk of over-anticoagulation and hemorrhage, more studies are needed

Question 28

VKORC1 Group A Haplotype is found the most in what population? Lowest in what?

Answer 28

Highest = Asian Lowest = AA

Question 29

VKORC1 Group B Haplotype is found the most in what population? Lowest in what?

Answer 29

Highest = European and AA Lowest = Asian

Question 30

What variation in AA have been associated w/ an increase in dosing requirements?

Answer 30

CALU (Calumenin)

Question 31

What specific factors are addressed in the package insert?

Answer 31

CYP2C9 and VKORC1

Question 32

What codes for OATP1B1, a hepatic transporter? Which variant results in decreased activity?

Answer 32

SCLO1B1 *15

Question 33

What are some characteristics of familial hypercholesterolemia?

Answer 33

1. High LDL 2. Heterozygous 3. Mutation in LDL, APOB, or PCSK9

Question 34

What are some issues with diagnosing familial hypercholesterolemia?

Answer 34

1. Hard to test; too many mutations 2. Highly under-diagnosed in US 3. Higher diagnosis rate in countries performing cascade testing

Question 35

Adding isosorbide dinitrate/hydralazine benefits who?

Answer 35

Ppl w/ heart failure + AA

Question 36

CYP11B2 homo and hetero GOF in found mainly in what population? What is its significance?

Answer 36

Caucasian Associated w/ more heart failure

Question 37

Mature-onset diabetes of the young is (monogenic/polygenic)

Answer 37

monogenic

Question 38

What is the most common genetic mutation of mature-onset diabetes of the young?

Answer 38

HNF1A

Question 39

What has been the treatment of choice (over insulin) for mature-onset diabetes of the young?

Answer 39

Sulphonylureas

Question 40

Understanding of mature-onset diabetes of the young has led to what kind of theories?

Answer 40

Gene theories of Type II Diabetes mellitus

Question 41

Which genetic homozygote demonstrates clinically significant outcomes with sulphonylureas?

Answer 41

CYP2C9 LOF

Question 42

CYP2C9 (LOF vs GOF) is more likely to achieve goal HbA1C, but have a higher risk of what?

Answer 42

LOF Higher risk of hypoglycemia

Question 43

What are the non-genetic factors predicting metformin intolerance?

Answer 43

1. Increased age 2. Females 3. OCT1-inhibitor drug interaction

Question 44

ATM and Metformin ATM gene codes for what?

Answer 44

Serine/threonine kinase