Genetic Variations in Individuals and Populations

Question 1

Optimizing drug therapies in the face of genetic variation

Answer 1

Pharmacogenetics and pharmacogenomics

Question 2

The study of inherited differences (variation) in drug metabolism and response

Answer 2

Pharmacogenetics

Question 3

Genetic variability can affect

Answer 3

Pharmacokinetics and pharmacodynamics

Question 4

Clearance/excretion, metabolism, transportation, and absorption of drug

Answer 4

Pharmacokinetics

Question 5

Drug activity and interaction with downstream targets

Answer 5

Pharmacodynamics

Question 6

Pharmacogenetics encompasses

Answer 6

1. ) Pharmacokinetics

2. ) Pharmacodynamics

Question 7

A ‘genomic’ approach to pharmacogenetics –using GWAS to assess the impact of an ensemble of SNPs on the impact of drug therapy

Answer 7

Pharmacogenomics

Question 8

Genome wide association study

Answer 8

GWAS

Question 9

Single nucleotide polymorphism

Answer 9

SNPs

Question 10

How do we find the international normalized ratio (INR)?

Answer 10

INR = PTobs / PTnormal

where,

PT = Prothrombin time

Question 11

What is the normal Prothrombin Time (PT)?

Answer 11

11.0-13.5 seconds

Question 12

56 enzymes, each encoded by a separate gene. All are heme-containing proteins expressed primarily in the liver. Responsible for detoxifying and exporting both endogenous and xenobiotic compounds

Answer 12

Cytochrome P450 (CYP)

Question 13

CYP’s can also activate

Answer 13

Drugs

Question 14

Accept electrons from donors such as NADPH to catalyze a number of different reactions, most importantly the addition of oxygen to C, N, or S atoms

Answer 14

CYPs

Question 15

Phase I of drug metabolism by CYP is

Answer 15

Hydroxylation of molecule

Question 16

Functionalization of the hydroxyl group by a sugar or acetyl group, increasing drug solubility and allowing it to be excreted

Answer 16

Phase II of drug metabolism by CYP

Question 17

Which CYPs react with Xenobiotics?

Answer 17

CYP 1, 2, and 3

Question 18

Six genes in particular: CYP1, CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are responsible for the metabolism of 90% of commonly used

Answer 18

Drugs

Question 19

Which is the most active CYP in common drug metabolism?

Answer 19

CYP3A4

Question 20

Used in the prevention of thrombosis, embolism in cases of heart valve prosthesis, recurrent stroke, DVT, and pulmonary embolism

-2 million prescriptions per year

Answer 20

Warfarin (coumadin)

Question 21

Impairs the synthesis of vitamin K dependent clotting factors

Answer 21

Warfarin (coumadin)

Question 22

Warfarin inhibits a key enzyme in vitamin K recycling called

Answer 22

Vitamin K Epoxide Reductase

Question 23

How many major sites of modification by CYPs are there on warfarin?

Answer 23

Five (C’s 4, 6, 7, 8, and 10)

Question 24

Warfarin metabolized in the liver cell by C7 hydroxylation or C6 hydroxylation by CYP2C9

Answer 24

S-Warfarin

Question 25

There is significant variation in the individual activity levels of

Answer 25

Cytochrome P450s

Question 26

Is the CYP2C9 interaction with warfarin considered a component of Pharmacokinetics or Pharmacodynamics?

Answer 26

Pharmacokinetics

Question 27

The action of drugs in the body over a period of time, including the processes of absorption, distribution, and localization in tissues

Answer 27

Pharmacokinetics

Question 28

Classified as poor, normal, or ultrafast metabolizers

Answer 28

CYP variants

Question 29

Which CYP2C9 variant has a 25% dose reduction?

Answer 29

CYP2C9*2

Question 30

Which CYP2C9 variant has a 35% dose reduction?

Answer 30

CYP2C9*3

Question 31

What is the recommended target therapeutic range for INR?

Answer 31

INR = 2.0 - 3.0

Question 32

CYP variants are classified as

Answer 32

Poor (PM), Normal (intermediate, IM), or Ultrafast (extensive, EM) metabolizers

Question 33

In the CYP2C9 family, what is an extensive metabolizer?

Answer 33

Wild type: CYP2C9*1*1

Question 34

In the CYP2C9 family, what are intermediate metabolizers?

Answer 34

*1*2 and *1*3 variants

Question 35

In the CYP2C9 family, what are poor metabolizers?

Answer 35

*2*2, *2*3, and *3*3 variants

Question 36

Vitamin K epoxide reductase (gene: VKORC1) is a target of

Answer 36

Warfarin

Question 37

Inhibition of VKORC1 by warfarin prevents regeneration of reduced vitamin K, which is necessary for gamma glutamyl carboxylation of

Answer 37

Coagulation factors

Question 38

Prevents regeneration of reduced vitamin K, which is necessary for gamma glutamyl carboxylation of coagulation factors

Answer 38

Inhibition of VKORC1 by warfarin

Question 39

Single nucleotide polymorphisms (SNPs) in VKORC1 correlate with

Answer 39

Warfarin sensitivity

Question 40

Is the VKORC1 interaction with warfarin considered a component of pharmacokinetics or pharmacodynamics?

Answer 40

Pharmacodynamics

Question 41

Deals with drug activity and interaction with downstream targets

Answer 41

Pharmacodynamics

Question 42

Combinations of alleles or genetic markers which occur more or less frequently than expected at random

Answer 42

Linkage Disequilibrium

Question 43

Account for approximately 30% of variation in Warfarin sensitivity

Answer 43

VKORC1 + CYP2C9

Question 44

Accounts for another 1-2% of warfarin sensitivity (according to a GWAS study of 2000 patients)

Answer 44

CYP4F2

Question 45

SNPs in CYP2C18 and CYP2C19 also correlate with a

Answer 45

Warfarin sensitivity

Question 46

Codeine intoxication is associated with ultra-rapid

Answer 46

CYP2D6 metabolism

Question 47

A study found that there are 3+ copies of the CYP2D6 allele, which indicates

Answer 47

Gene duplication

Question 48

It was then found that naturally occurring variation in CYP3A4 has no observable effect on

Answer 48

Optimal codeine dosage

Question 49

The combination of the gene duplication in CYP2D6 and the natural variation in CYP3A4 resulted in ultra-rapid conversion of codeine to

Answer 49

Morphine - 10%converted by CYP2D6 - 80% cleared by CYP3A4

Question 50

Have provided valuable data in the areas of pharmacogenetics and pharmacogenomics. This is especially the case for adverse drug reactions attributable to alleles of a single gene, often one that encodes an enzyme contributing to metabolism of the drug.

Answer 50

Candidate-gene studies

Question 51

What are some of the factors that have limited GWA studies to date?

Answer 51

Sample size, phenotypic characterization, replication of findings, and effect size

Question 52

Encodes the main metabolizing enzyme for coumarin anticoagulants such as Warfarin

Answer 52

CYP2C9 gene

Question 53

Markers in which two genes are the main predictors for coumarin dosage?

Answer 53

VKORC1 and CYP2C9 genes

Question 54

Accounts for approximately 1.5% of warfarin dosage variability

Answer 54

CYP4F2 SNP

Question 55

When a higher dose is required for therapeutic affect

Answer 55

Tolerance

Question 56

When a lower dose is required for therapeutic affect

Answer 56

Intolerance/sensitivity

Question 57

Has nothing to do with the mechanism of action of the drug. -Just tells us how well the drug gets to its target

Answer 57

Pharmacokinetics (PK)

Question 58

Tells us about the drugs activity and how well it interacts with its downstream targets

Answer 58

Pharmacodynamics

Question 59

Tells us how quickly our blood clots

Answer 59

Prothrombin time (PT)

Question 60

The therapeutic window is an INR of 2-3, below the therapeutic window, the drug is not helpful. Above the therapeutic window, the drug is

Answer 60

Toxic

Question 61

CYPs are mostly expressed in the

Answer 61

Liver

Question 62

CYPs can activate drugs, an example of this is the activation of codeine to morphine by

Answer 62

CYP2D6

Question 63

The conversion of acetometophin to N-Acetyl-P-Benzoquinone imine by CYP3A4 is an example of how CYPs can be

Answer 63

Harmful

Question 64

We are given a racemic mixture of Warfarin, but which isomer is more active?

Answer 64

S-warfarin

Question 65

Processed by CYP2C9 into 7-hydroxywarfarin or 6-hydroxywarfarin

Answer 65

S-Warfarin

Question 66

Multi-drug transporters that will push all xenobiotics out of the cell

Answer 66

ABC transporters

Question 67

An example of pharmacokinetics because it deals with how the drug is distributed and how it is processed

Answer 67

CYP2C9 interaction with Warfarin

Question 68

The safe therapeutiv window represents

Answer 68

Pharmacodynamic effects

Question 69

An Arg-->Cys mutation that results in reduced affinity for P450 reductase, which makes you more sensitive to Warfarin -requires 25% lower dosage

Answer 69

CYP2C9*2

Question 70

An Ile-->Leu mutation that alters substrate specificity of CYP2C9 and will make you more sensitive to Warfarin -requires 35% lower dosage

Answer 70

CYP2C9*3

Question 71

Gamma glutamyl carboxylation is necessary for

Answer 71

Coagulation