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Pharm exam 5 > Pharmacogenetics/Pharmcogenomics > Flashcards

Pharmacogenetics/Pharmcogenomics Flashcards

1
Q

The study of the genetic basis for variations in drug
response. Typical used to define the study of how variation in single gene
influences the response to a single drug.

A

Pharmcogenetics

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2
Q

The study of how all of the genes (the genome) can

influence responses to drugs.

A

Pharmcogenomics

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3
Q

Variation in a single gene causing difference in specific drug response

A

monogenic drug response

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4
Q

Variations in multiple genes causing difference in a specific drug response

A

Multigenic drug response

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5
Q

Drug response is a complex interplay between environmental and genetic factors

A

gene-by-environment phenotype

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6
Q

role of the gut microbiome in pharmacological responses

A

Pharmacomicrobiomics

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7
Q

explain how microbes can affect pharamcomicrobiomics

A

Activate or inactive drugs

Generate toxic byproducts of drugs

Alter drug metabolism (direct and indirect)

E.g. enterohepatic cycling

  • Irinotecan is cleared by being glucuronidated in liver, excreted into intestine, and removed in feces
  • Some microbes living in intestines produce beta-glucuronidase
  • Reactivates irinotecan and causes toxicity (severe diarrhea)
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8
Q

Difference in DNA code that occurs in MORE THAN 1% of the population

A

Polymorphisms

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9
Q

Difference in DNA code that occurs in LESS THAN 1% of the population

A

mutation

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10
Q

Base pair change does not cause amino acid substitution

  • May result in decreased transcript stability or alter splicing
  • This can lead to changes in protein expression and/or function
A

Synonymous SNP

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11
Q

Base pair change leads to an amino acid substitution

- May result in change in protein structure, stability, substrate affinity, introduction of a stop codon

A

Nonsynonymous SNP

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12
Q

Most SNPs in human genome are found in regions of DNA that are _____

A

non-protein coding regions (enhancer, promoter, introns)

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13
Q

For noncoding SNPs there’s often no functional change

However can alter what?

A

Transcription factor binding

Splicing

Transcript stability

Enhancer function

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14
Q

Insertions/deletions (Indels):

Can lead to 1

  • change in 2 of a protein
  • introduction of a 3

Alter promoter or enhance and result in an increase 4

A
  1. frameshift
  2. AA sequence
  3. stop codon
  4. transcript quantity
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15
Q

___ refer to either complete deletion or duplication of a particular gene

Gain of function or loss of function

A

Copy number variations (CNV)

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16
Q

polymorphisms common across all ethnic groups

A

Cosmopolitan polymorphisms

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17
Q

polymorphisms that differ between groups (ethnic or race)

A

population polymorphisms

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18
Q

Phenotype-to-genotype approach

A. Start out by directly measuring 1 (e.g., the effect of warfarin on blood coagulation)

B. Group 2 and outliers

C. 3 individuals from each group to determine if polymorphisms account for phenotype groups

A
  1. pharmcogenetic trait
  2. normal responders
  3. Genotype
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19
Q

Pharmacogenetic trait: Any measurable trait associated with a drug

a. 1 activity
b. drug levels in 2
c. drug 3 in bodily fluids
d. 4 response (blood pressure)

A
  1. enzyme
  2. bodily fluids
  3. metabolites
  4. physiological
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20
Q

gene approach versus genome-wide approach

A. Determine polymorphisms by genotyping a SPECIFIC gene that is predicted to cause differences in pharmacogenetic trait between the two groups

B. Unbiased survey of ALL difference in ENTIRE genome between two groups

A

A = Candidate gene approach

B = Genome-wide approach

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21
Q

gene approach versus genome-wide approach

A. Does not require knowledge of cellular mechanism responsible for trait

B. Requires knowledge of cellular mechanism to choose gene to study

A

A = genome-wide approach

B = candidate gene approach

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22
Q

Disadvantage of candidate gene approach

A

wrong gene might be studied

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23
Q

disadvantage of genome-wide approach

A

identification of genetic differences that do not effect drug response

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24
Q

The effect of a polymorphism in a gene that codes for drug targets such as receptors or enzymes

Can impair or enhance drug binding

Alters drug response

pharmacodynamics, indirect or pharmcokinetics?

A

pharmacodynamics

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25
Q

The effect of a polymorphism in a gene or genes that regulate _____

Metabolic enzymes or drug transporters

Alters drug concentrations resulting in changes in therapeutic and adverse effects

pharmacodynamics, indirect or pharmcokinetics?

A

pharmacokinetics

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26
Q

The effects of polymorphisms in a gene that does not interact with the drug, not involved with disposition of the drug
- Effect on the biology of the individual affects the drug response or side effect

The effects of polymorphisms in a gene that does not interact with the drug, not involved with disposition of the drug
Effect on the biology of the individual affects the drug response or side effect

A

indirect

27
Q

what drugs use CYP2D6 (hepatic metabolism of 20% commonly used drugs)

A

Tamoxifen

codeine

paroxetine (SSRI)

28
Q

how do you get different phenotypes of CYP2D6

A

Ultrametabolizer - gene duplication, polymorphisms increasing activity

Poor metabolizer - both alleles have polymorphisms that inactive CYP2D6

29
Q

CYP2D6 converts codeine to what

A

morphine

30
Q

How does polymorphism of CYP2D6 effect tamoxifen, codeine, and paroxetine if there an ultrametabolizer?

A

Tamoxifen (prodrug) = increased response

Codeine (prodrug) = increased response

Paroxetine = decreased response

31
Q

what drugs does CYP2C19 metabolize

A

Clopidogrel

Omeprazole (PPI)

Lansoprazol (PPI)

32
Q

How does CYP2C19 polymorphism effect clopidogrel and omeprazole, lansoprazol if they’re an ultrametabolizer

A

Clopidogrel = increase

Omeprazole and Lansoprazol = decrease (poor metabolizers have a higher cure rate than extensive/aka normal metabolizers)

33
Q

CYP2C9 polymorphism effect on warfarin

A

Polymorphisms cause reduced function

  • metabolize warfarin slowly
  • lower dose required
  • greater risk for bleeding
  • longer duration to dose stabilization
34
Q

effect of VKORC1 polymorphism on warfarin?

A

less vit K dependent clotting factors produced

lower warfarin dose necessary to achieve therapeutic effect

35
Q

what polymorphisms can effect 5-flurouracil in cancer treatment

A

DPD (Dihydropyrimidine dehydrogenase)

TYMS (thymidylate synthetase)

36
Q

what polymorphisms can effect6-MP in cancer treatment

A

TPMT (Thiopurine methyltransferase)

37
Q

does poymorphism of DPD cause lower or higher toxicity of 5-FU

A

higher toxicity (DPD inactivates 5-FU)

38
Q

5-FU is metabolized into FdUMP, which inhibits what?

A

thymidylate synthase

39
Q

what does dihydropyrimidine dehydrogenase (DPD) due with 5-FU

A

inactivates 5-FU

40
Q

For 5-FU tx, insertion polymorphism in enhancer region can cause was to thymidylate synthetase activity

A

increases (3 tandem repeats) or decreases (2 tandem repeats)

decrease activity = good antitumor response

41
Q

what does TPMT (thiopurine methyltrasferase) do to 6-MP

A

inactivates 6-MP

42
Q

does polymorphism in TPMT cause an increase or decrease in toxicity

A

increase

43
Q

SNP on gene in what chromosome has an association with simvastatin-induced myopathy

A

12

44
Q

what gene has an impact on the uptake of simvastatin?

A

Solute Carrier Organic Anion Transporter 1B1 (SLCO1B1)

45
Q

what is the effect if someone has a polymorphism in Solute Carrier Organic Anion Transporter 1B1 (SLCO1B1) where valine is replaced with alanin

  • effecting liver uptake of simvastatin
A

Decreased transport

T/T (valine/valine) = normal transport

T/C = decreased

C/C (alanine/alanine) = low

46
Q

what is the effect of having polymorphisms in estrogen receptor ERalpha

A

homozygotes has a greater increase in HDL levels following hormone replacement therapy

47
Q

what polymorphism effects albuterol use

A

16th AA acid residue of ADRB2

48
Q

what polymorphisms can increase risk of venous thromboembolism with oral contraceptives?

A

Factor V and prothrombin

49
Q

Individuals with what allele have a high risk of having a hypersensitivity reaction to abacavir (ABC) - e.g. SJS

ABC = reverse transcriptase inhibitor

A

HLA-B57:01

50
Q

what polymorphism can effect alzheimer’s therapy

A

APOE

  • absence of certain alleles in APOE gene correlate with better therapeutic success with tacrine
51
Q

Genome-wide association studies showed the SNP polymorphisms in ____ gene predicted response to interferon-α treatment (HBV and HCV tx)

A

IL-28

52
Q

what alleles in IL-28B had a favorable and unfavorable phenotype for interfer on alpha tx

A

CC = favorable

CT or TT = unfavorable

53
Q

is CYP2D6 gene polymorphism pharmacokinetic or pharmacodynamic (tomoxifen, codeine, paroxetine)

A

pharmacokinetic

54
Q

is CYP2C19 gene polymorphism pharmacokinetic or pharmacodynamic (Clopidogrel, Omeprazole)

A

pharmacokinetic

55
Q

is CYP2C9 gene polymorphism for Warfarin pharmacokinetic or pharmacodynamic

A

pharmcokinetic

56
Q

is VKOR gene polymorphism for Warfarin pharmacokinetic or pharmacodynamic

A

pharmacodynamic

57
Q

is SLCO1B1 gene polymorphism for Simvastatin pharmacokinetic or pharmacodynamic

A

pharmacokinetic

58
Q

is DPD gene polymorphism for 5-FU pharmacokinetic or pharmacodynamic

A

pharmacokinetic

59
Q

is TYMS (TS) gene polymorphism for 5-FU pharmacokinetic or pharmacodynamic

A

pharmacodynamic

60
Q

is TPMT gene polymorphism for 6-MP pharmacokinetic or pharmacodynamic

A

pharmcokinetic

61
Q

is ERalpha gene polymorphism for estrogen/progesterone pharmacokinetic or pharmacodynamic

A

pharmacodynamic

62
Q

is ADRB2 gene polymorphism for albuterol pharmacokinetic or pharmacodynamic

A

pharmacodynamic

63
Q

what genes and drugs have an indirect phenotype

A

HLA-B with abacavir

IL28B with interferon-alpha

Pharm exam 5 (9 decks)

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