Pharmacogenetics/Pharmcogenomics Flashcards
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.
Pharmcogenetics
The study of how all of the genes (the genome) can
influence responses to drugs.
Pharmcogenomics
Variation in a single gene causing difference in specific drug response
monogenic drug response
Variations in multiple genes causing difference in a specific drug response
Multigenic drug response
Drug response is a complex interplay between environmental and genetic factors
gene-by-environment phenotype
role of the gut microbiome in pharmacological responses
Pharmacomicrobiomics
explain how microbes can affect pharamcomicrobiomics
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)
Difference in DNA code that occurs in MORE THAN 1% of the population
Polymorphisms
Difference in DNA code that occurs in LESS THAN 1% of the population
mutation
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
Synonymous SNP
Base pair change leads to an amino acid substitution
- May result in change in protein structure, stability, substrate affinity, introduction of a stop codon
Nonsynonymous SNP
Most SNPs in human genome are found in regions of DNA that are _____
non-protein coding regions (enhancer, promoter, introns)
For noncoding SNPs there’s often no functional change
However can alter what?
Transcription factor binding
Splicing
Transcript stability
Enhancer function
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
- frameshift
- AA sequence
- stop codon
- transcript quantity
___ refer to either complete deletion or duplication of a particular gene
Gain of function or loss of function
Copy number variations (CNV)
polymorphisms common across all ethnic groups
Cosmopolitan polymorphisms
polymorphisms that differ between groups (ethnic or race)
population polymorphisms
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
- pharmcogenetic trait
- normal responders
- Genotype
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)
- enzyme
- bodily fluids
- metabolites
- physiological
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 = Candidate gene approach
B = Genome-wide approach
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 = genome-wide approach
B = candidate gene approach
Disadvantage of candidate gene approach
wrong gene might be studied
disadvantage of genome-wide approach
identification of genetic differences that do not effect drug response
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?
pharmacodynamics
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?
pharmacokinetics
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
indirect
what drugs use CYP2D6 (hepatic metabolism of 20% commonly used drugs)
Tamoxifen
codeine
paroxetine (SSRI)
how do you get different phenotypes of CYP2D6
Ultrametabolizer - gene duplication, polymorphisms increasing activity
Poor metabolizer - both alleles have polymorphisms that inactive CYP2D6
CYP2D6 converts codeine to what
morphine
How does polymorphism of CYP2D6 effect tamoxifen, codeine, and paroxetine if there an ultrametabolizer?
Tamoxifen (prodrug) = increased response
Codeine (prodrug) = increased response
Paroxetine = decreased response
what drugs does CYP2C19 metabolize
Clopidogrel
Omeprazole (PPI)
Lansoprazol (PPI)
How does CYP2C19 polymorphism effect clopidogrel and omeprazole, lansoprazol if they’re an ultrametabolizer
Clopidogrel = increase
Omeprazole and Lansoprazol = decrease (poor metabolizers have a higher cure rate than extensive/aka normal metabolizers)
CYP2C9 polymorphism effect on warfarin
Polymorphisms cause reduced function
- metabolize warfarin slowly
- lower dose required
- greater risk for bleeding
- longer duration to dose stabilization
effect of VKORC1 polymorphism on warfarin?
less vit K dependent clotting factors produced
lower warfarin dose necessary to achieve therapeutic effect
what polymorphisms can effect 5-flurouracil in cancer treatment
DPD (Dihydropyrimidine dehydrogenase)
TYMS (thymidylate synthetase)
what polymorphisms can effect6-MP in cancer treatment
TPMT (Thiopurine methyltransferase)
does poymorphism of DPD cause lower or higher toxicity of 5-FU
higher toxicity (DPD inactivates 5-FU)
5-FU is metabolized into FdUMP, which inhibits what?
thymidylate synthase
what does dihydropyrimidine dehydrogenase (DPD) due with 5-FU
inactivates 5-FU
For 5-FU tx, insertion polymorphism in enhancer region can cause was to thymidylate synthetase activity
increases (3 tandem repeats) or decreases (2 tandem repeats)
decrease activity = good antitumor response
what does TPMT (thiopurine methyltrasferase) do to 6-MP
inactivates 6-MP
does polymorphism in TPMT cause an increase or decrease in toxicity
increase
SNP on gene in what chromosome has an association with simvastatin-induced myopathy
12
what gene has an impact on the uptake of simvastatin?
Solute Carrier Organic Anion Transporter 1B1 (SLCO1B1)
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
Decreased transport
T/T (valine/valine) = normal transport
T/C = decreased
C/C (alanine/alanine) = low
what is the effect of having polymorphisms in estrogen receptor ERalpha
homozygotes has a greater increase in HDL levels following hormone replacement therapy
what polymorphism effects albuterol use
16th AA acid residue of ADRB2
what polymorphisms can increase risk of venous thromboembolism with oral contraceptives?
Factor V and prothrombin
Individuals with what allele have a high risk of having a hypersensitivity reaction to abacavir (ABC) - e.g. SJS
ABC = reverse transcriptase inhibitor
HLA-B57:01
what polymorphism can effect alzheimer’s therapy
APOE
- absence of certain alleles in APOE gene correlate with better therapeutic success with tacrine
Genome-wide association studies showed the SNP polymorphisms in ____ gene predicted response to interferon-α treatment (HBV and HCV tx)
IL-28
what alleles in IL-28B had a favorable and unfavorable phenotype for interfer on alpha tx
CC = favorable
CT or TT = unfavorable
is CYP2D6 gene polymorphism pharmacokinetic or pharmacodynamic (tomoxifen, codeine, paroxetine)
pharmacokinetic
is CYP2C19 gene polymorphism pharmacokinetic or pharmacodynamic (Clopidogrel, Omeprazole)
pharmacokinetic
is CYP2C9 gene polymorphism for Warfarin pharmacokinetic or pharmacodynamic
pharmcokinetic
is VKOR gene polymorphism for Warfarin pharmacokinetic or pharmacodynamic
pharmacodynamic
is SLCO1B1 gene polymorphism for Simvastatin pharmacokinetic or pharmacodynamic
pharmacokinetic
is DPD gene polymorphism for 5-FU pharmacokinetic or pharmacodynamic
pharmacokinetic
is TYMS (TS) gene polymorphism for 5-FU pharmacokinetic or pharmacodynamic
pharmacodynamic
is TPMT gene polymorphism for 6-MP pharmacokinetic or pharmacodynamic
pharmcokinetic
is ERalpha gene polymorphism for estrogen/progesterone pharmacokinetic or pharmacodynamic
pharmacodynamic
is ADRB2 gene polymorphism for albuterol pharmacokinetic or pharmacodynamic
pharmacodynamic
what genes and drugs have an indirect phenotype
HLA-B with abacavir
IL28B with interferon-alpha
