36 Personalized medicine in cardiovascular disease

Question 1

Genotyping HLA-B*57:01 is used for what drug adverse drug reactions in HIV?

Answer 1

The HLA-B*57:01 allele has been associated with hypersensitivity to abacavir, a highly effective nucleoside analog reverse-transcriptase inhibitor used to treat HIV infection and AIDS

Question 2

Crizotinib, a TKI

Answer 2

1) Crizotinib is a receptor tyrosine kinase inhibitor (TKI) that blocks cell signaling by tyrosine kinases ALK, hepatocyte growth factor receptor (HGFR, c-Met) and Recepteur d’Origine Nantais (RON);

2) Crizotinib showed marked antitumor activity in patients with advanced ALK-positive non–small-cell lung cancer

Question 3

Warfarin used in which diseases?

Answer 3

1) Warfarin is anticoagulant drug;
2) used in the prevention and treatment of venous thrombosis, pulmonary embolism, and the complications associated with atrial fibrillation and/or cardiac valve replacement;
3) Warfarin is sometimes prescribed to reduce the risk of stroke after a myocardial infarction (MI)

Question 4

Which enzyme Warfarin inhibits?

Answer 4

1) Warfarin inhibits the enzyme VKORC1;
2) VKORC1catalyzes the conversion of vitamin K epoxide to the active reduced form of
vitamin K, vitamin K hydroquinone.
3) Vitamin K hydroquinone is an essential cofactor in the synthesis of several clotting factors—it promotes the synthesis of γ-carboxyglutamic
acid residues in the proteins essential for biological activity.
4) the decreased availability of
vitamin K hydroquinone leads to decreased activity of the clotting factors II, VII, IX, and
X, and the anticoagulant proteins C and S

Question 5

Warfarin stable dose

Answer 5

WSD: 06 to 15.5 mg/day

Question 6

what is VKORC1?

Answer 6

1) vitamin K epoxide reductase complex subunit 1;
2) Warfarin targets VKORC1, which catalyzes the rate limiting step of vitamin K cycle.

Question 7

VKORC1 mutation may cause the need of lowered warfarin WSD

Answer 7

1) A common non-coding variant of VKORC1, -1639G>A, increased sensitivity to warfarin;
2) this SNP occurs in the promoter region of VKORC1 and alters a transcription factor binding site, leading to lower protein expression.
3) lowered WSD;
4) the −1639G>A allele frequency varies among different ethnic groups. It is the major allele
(around 90%) in Asian populations, and may be a contributing factor for lower warfarin
dosing requirements often observed in patients of Asian descent. It is also common in
Caucasians (around 40%) and African Americans (around 14%).

Question 8

VKORC1 mutation associated with warfarin resistance

Answer 8

D36Y, rare, higher WSD needed

Question 9

epigenetic regulation of VKORC1

Answer 9

microRNA: miR-133a, leads to decreased VKORC1 expression

Question 10

Two isoforms of Warfarin

Answer 10

1) S-warfarin, more potent than R-warfarin;
2) R-warfarin

Question 11

Main CYP450 isozymes involved in the metabolism of warfarin

Answer 11

CYP2C9, CYP3A4, CYP1A2;

CYP2C9 metabolizes S-warfarin;
CYP3A4, CYP1A2 metabolizes R-warfarin;

Question 12

CYP2C9 alleles affecting warfarin metabolism

Answer 12

1) CYP2C91 : wild-type allele, normal enzyme activity, normal metabolizer phenotype.
2) CYP2C92 (Arg144Cys) and CYP2C9*3 (Ile359Leu): reduced enzyme activity, patients are more sensitive to warfarin, reduced WSD

Question 13

CYP2C9*2 ethnic group distribution

Answer 13

Caucasian (10-20%) ;
Asian (1-3%);
African (0-6%);

Question 14

CYP2C9*3 ethnic group distribution

Answer 14

CYP2C9*3 allele is less common (<10% in most populations), more in Caucasian, rare in others

Question 15

In African Americans, which CYP2C9 variants contribute to the variability in patient response
to warfarin?

Answer 15

1) CYP2C9*5, *6, *8, and *11;
2) 20% of African-American carry at least one

Question 16

CYP2C92 and CYP2C93 affect which warfarin isoform metabolism?

Answer 16

S-warfarin, need to decrease WSD

Question 17

Genetic tests for CYP2C9 and VKORC1

Answer 17

The variants that are routinely
tested for are CYP2C92, CYP2C93, and −1639G>A.
These variants are used in the FDA table to guide therapy, and also in the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm.

Question 18

CYP2C9*2

Answer 18

CYP2C9*2: 430C>T; Arg144Cys

Question 19

CYP2C9*3

Answer 19

CYP2C9*3: 1075A>C; Ile359Leu

Question 20

CYP4F2 and variant affect warfarin WSD

Answer 20

1) CYP4F2 metabolizes reduced vitamin K to hydroxy-vit K;
2) novel mutation: 1397 G>A, needs higher WSD, observed more in Caucasian and Asian not in African-American.

Question 21

Clopidogrel (Clo-pi-DOG-rel)

Answer 21

1) antiplatelet medication;
2) prevents platelets from sticking together, forming dangerous clots

Question 22

Clopidogrel is metabolized by two main groups of enzymes.

Answer 22

1) Carboxylesterase (CES1): 85% of clopidogrel is hydrolyzed by hepatic CES1 to inactive form;
2) CYP system: 15% of clopidogrel is oxidized by CYPs to produce the active 5-thiol metabolite: CYP1A2, CYP3A4/5, CYP2B6, CYP2C9, CYP2C19.

Note: 5-thiol metabolite inhibits platelet purinergic P2Y12 receptor, preventing ADP-induced platelet aggregation.

Question 23

Main CYP enzyme for clopidogrel conversion to its active form.

Answer 23

CYP2C19 is the principle enzyme responsible for converting clopidogrel into its active metabolite

Question 24

4 main CYP2C19 gene alleles and clopidogrel metabolism

Answer 24

1) CYP2C191: wild type, normal CYP2C19 function, normal metabolism;
2) CYP2C192: 681G>A, no or reduced or loss CYP2C19 function, intermediate or poor metabolism;
3) CYP2C193: 636G>A, no or reduced or loss CYP2C19 function, intermediate or poor metabolism;
4) CYP2C1917: -806C>T, gain of CYP2C19 function, rapid or ultra-rapid metabolism

Question 25

5 main CYP2C19 genotype and phenotype of clopidogrel metabolism

Answer 25

1) CYP2C191/1: normal clopidogrel metabolizer;
2) CYP2C191/2, 1/3: intermediate clopidogrel metabolizer;
3) CYP2C192/2, 2/3: poor clopidogrel metabolizer;
4) CYP2C191/17: rapid clopidogrel metabolizer;
5) CYP2C1917/17: ultra-rapid clopidogrel metabolizer

Question 26

Carboxylesterase 1

Answer 26

CES1;

Hydrolyzes clopidogrel to release an inactive metabolite clopidogrel carboxylic acid (CCA)

Question 27

1) Mutation of CES1 and clopidogrel metabolism

Answer 27

CES1 G143E is associated with increased clopidogrel active metabolite levels and greater clopidogrel response.

may increase bleeding by reducing the ADP-induced platelet aggregation.

Question 28

2) Mutation of CES1 and clopidogrel metabolism

Answer 28

1) CES1 A2: A(-816)C;
2) an SNP in the promoter region;
3) increased CES1 transcription;
4) increased ex vivo platelet reactivity;
5) increased clopidogrel metabolism and elimination

Question 29

miRNA-223 may repress platelet P2Y12 mRNA expression, decrease platelet reactivity in patients with P2Y12 inhibitors such as clopidogrel

Question 30

Patients with CYP2C19 intermediate or poor metabolizer can use alternative drugs of clopidogrel

Answer 30

Prasugrel;
Ticagrelor

Question 31

Statins

Answer 31

1) Statins are used to treat high cholesterol;
2) Statins are hypolipidemic drugs;
3) Statins are Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors

Question 32

Adverse drug reactions (ADRs) of statins

Answer 32

1) myalgias;
2) severe myopathies with increased creatine kinase levels;
3) potential fatal rhabdomyolysis;
4) rare autoimmune-mediated necrotizing myositis

Question 33

SLCO1B1 gene

Answer 33

1) encodes organic anion transporting polypeptide 1B1, or OATP1B1;

2) OATP1B1 is found in liver cells; it transports compounds from the blood into the liver so that they can be cleared from the body.

3) OATP1B1 is the major uptake protein for statin into the liver.

Question 34

SLCO1B1c.521T>C causes muscle ADRs in patients using statins

Answer 34

1) SLCO1B1 c.521T>C, common in Asians and Caucasians, CC homozygous reduce nonrenal clearance, causing muscle ADRs;
2) SLCO1B1 c.521T>C decreased OPTP1B1 expression on the cell surface, total protein is not affected though.
3) c.521T > C, p.Val174Ala

Question 35

SLCO1B1c.388A>G causes muscle ADRs in patients using statins

Answer 35

1) SLCO1B1c.388A>G increases OATP1B1 expression;
2) Asparagine to Aspartic acid at 130 position: p.Asn130Asp;
3) SLCO1B1c.388A>G is common is African-Americans than in Caucasians

Question 36

4 distinct OATP1B1 haplotypes for statin metabolism

Answer 36

1) OATP1B15: 388A/521C, impaired hepatic uptake, increased statin exposure systemically;
2) OATP1B115: 388G/521C, impaired hepatic uptake, increased statin exposure systemically;
3) OATP1B11B: 388G/521T, increased statin hepatic uptake, reduced statin exposure systemically;
4) OATP1B11A: 388A/521T, normal allele, wild type

Question 37

Rotor syndrome

Answer 37

1) an affected individual must have mutations in both the SLCO1B1 and the SLCO1B3 gene;
2) an autosomal recessive ;
3) The SLCO1B1 and SLCO1B3 gene mutations that cause Rotor syndrome, lead to abnormally short, nonfunctional OATP1B1 and OATP1B3 proteins or an absence of these proteins;
4) characterized by conjugated hyperbilirubinemia, strongly reduced liver uptake of many compounds, jaundice.

Question 38

OATP1B1, 521T>C

Answer 38

1) statin ADRS are seen with simvastatin and atorvastatin, but not associated with pravastatin;
2) gender also plays a role

Question 39

Bucindolol

Answer 39

Bucindolol is a non-selective beta–adrenoreceptor (b-AR) inhibitor, also weakly inhibits alpha1-AR.

Question 40

Mutations in genes affecting bucindolol function

Answer 40

1) ADRB1 Arg389Gly;
2) ADRA2C Ins322-325Del polymorphism

Question 41

ADRB1 Arg389Gly homozygotes
and
any ADRA2C Ins322-325Del

Answer 41

enhance bucindolol effect

Question 42

ADRB1 Arg389Gly carriers (heterozygotes)
and
any ADRA2C Ins322-325Ins homozygotes

Answer 42

intermediate bucidolol effect

Question 43

ADRB1 Arg389Gly carriers (heterozygotes)
and
any ADRA2C Del22-325 carriers

Answer 43

No bucindolol effect