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Genomics > Cardiovascular Disease > Flashcards

Cardiovascular Disease Flashcards

1
Q

Active efflux of clopidogrel is thru what?

A

ABCB1

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2
Q

Degradation of clopidogrel is by what?

A

Intestinal esterases

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3
Q

How is clopidogrel activated?

A

Activated to active metabolite via 2 steps

  1. CYP2C19
  2. Possibly PON1
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4
Q

What is the target site of clopidogrel?

A

P2Y12, located on platelets

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5
Q

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

A

It occurs in both steps of metabolic activation

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6
Q

What are the genetic variations of CYP2C19?

A

Loss of function alleles (*2 and *3)

Gain of function allele (*17)

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7
Q

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

A

Caucasian to AA to Asian

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8
Q

CYP2C19*3 is exclusively in what population?

A

Asian

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9
Q

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

A

Increased odds of cardiac events and stent thrombosis

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

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10
Q

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

A

Failed to replicate any impact on outcome or surrogate clinical markers

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11
Q

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

A
  1. Diet
  2. ABCB1/CYP2C19 polymorphism and PON1
  3. Smoking
  4. Drug-drug interactions (notably PPIs)
  5. Intrinsic variation in platelet function
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12
Q

For poor metabolizers of CYP2C19, what must FDA require?

A

Black box warning regarding diminished effect of clopidogrel

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13
Q

For intermediate metabolizers of CYP2C19, what must FDA require?

A

They dont address it like poor metabolizers

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14
Q

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

A

Likelihood of Tx failure

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15
Q

How does warfarin work?

A

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

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16
Q

(R or S)-warfarin is more potent

A

S

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17
Q

(R or S)-warfarin is metabolized via CYP2C9

A

S

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18
Q

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

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

**AA only (5.7%)

19
Q

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

A

Decrease clearance by 40 to 75%

20
Q

What is the most and least common CYP2C9 allele?

A

Most common (69%) = Wildtype

Least common (6%) = Homo LOF

21
Q

Which genotype decreases warfarin clearance by 40 to 75%?

A

CYP2C9*2 and *3

22
Q

What are the VKORC1 haplotypes?

A

Group A and B

23
Q

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

A

lower

24
Q

Haplotype Group A includes what kind of haplotypes?

A

H1 and H2

25
Q

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

A

higher

26
Q

Haplotype Group B includes what kind of haplotypes?

A

H2, H8, and H9

27
Q

What population is CYP4F23/3 allele found in?

What is its significance?

A

Caucasians, rare in AA

Decrease risk of over-anticoagulation and hemorrhage, more studies are needed

28
Q

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

A

Highest = Asian

Lowest = AA

29
Q

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

A

Highest = European and AA

Lowest = Asian

30
Q

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

A

CALU (Calumenin)

31
Q

What specific factors are addressed in the package insert?

A

CYP2C9 and VKORC1

32
Q

What codes for OATP1B1, a hepatic transporter?

Which variant results in decreased activity?

A

SCLO1B1

*15

33
Q

What are some characteristics of familial hypercholesterolemia?

A
  1. High LDL
  2. Heterozygous
  3. Mutation in LDL, APOB, or PCSK9
34
Q

What are some issues with diagnosing familial hypercholesterolemia?

A
  1. Hard to test; too many mutations
  2. Highly under-diagnosed in US
  3. Higher diagnosis rate in countries performing cascade testing
35
Q

Adding isosorbide dinitrate/hydralazine benefits who?

A

Ppl w/ heart failure + AA

36
Q

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

A

Caucasian

Associated w/ more heart failure

37
Q

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

A

monogenic

38
Q

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

A

HNF1A

39
Q

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

A

Sulphonylureas

40
Q

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

A

Gene theories of Type II Diabetes mellitus

41
Q

Which genetic homozygote demonstrates clinically significant outcomes with sulphonylureas?

A

CYP2C9 LOF

42
Q

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

A

LOF

Higher risk of hypoglycemia

43
Q

What are the non-genetic factors predicting metformin intolerance?

A
  1. Increased age
  2. Females
  3. OCT1-inhibitor drug interaction
44
Q

ATM and Metformin

ATM gene codes for what?

A

Serine/threonine kinase

Genomics (11 decks)

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