EXAM #5: PHARMACOGENOMICS Flashcards
What is the monogenic drug response?
Variation in a SINGLE gene that alters a drug response
What is a multigenic drug response?
Variation in MULTIPLE genes alters drug response
What is the “gene-by-environment” phenotype?
General principle that drug response is an interplay between environment and genetic factors
What is the definition of a polymorphism?
A change in DNA code that occurs in MORE THAN 1% of the population
In contrast to a mutation, which occurs in less than 1% of the population.
What is an allele?
One of a number of alternate forms of a gene
*You have two alleles of genes, one from Dad and one from Mom
What is a SNP?
Single Nucleotide Polymorphism
A single nucleotide in a gene is changed
What is a Synonymous SNP? Does this result in changes in protein expression?
Base pair change that does NOT cause amino acid substitution
*YES!–can alter splicing
What is a Nonsynonymous SNP?
Base pair change that DOES result in amino acid substitution
What is an Indel?
Insertion or deletion i.e. addition or loss of genetic material
What can an indel result in?
Frameshift mutation
List three outcomes of an indel.
1) Change in amino acid sequence and protein structure
2) Introduction of a stop codon
3) Altered promoter/ enhancer activity
What is a copy number variation?
The deletion or duplication of AN ENTIRE GENE
*Lead to gain or function or loss of function phenotypes
What is the difference between a Cosmopolitan and Population polymorphism?
Cosmopolitan= common across all ethnic groups
Population= polymorphisms that differ between ethnicity and race
What is the phenotype-to-genotype approach?
1) Start by measuring a pharmacogenetic trait
2) Group individuals with the same pharmacogenetic responses
3) Genotype the patients
What is a pharmacogenetic trait?
Any measurable trait associated with a drug
- Enzyme activity
- Drug levels
- Drug metabolite
- Physiologic response
Note that the pharmacogentic trait is the RESPONSE to the drug
What are the advantages of measuring pharmacogenetic traits? What is the disadvantage?
Allows for measurement of ALL genes that give rise to a effect
*BUT also allows for non-genetic influences
What is the candidate gene approach to pharmacogenomics? List the advantages and disadvantages.
Determine polymorphisms by geotyping a SPECIFIC gene that is predicted to account for phenotypic differences
- Requires knowledge of underlying mechanism
- May study wrong gene
What is the genome-wide approach to pharmacogenomics? List the advantages and disadvantages.
Genotype everything and then select genes that account for phenotypic differences
- No knowledge of mechanism required
- Unbiased
- BUT at times, too much information
What is a polymorphism that effects pharmacokinetics going to alter?
Metabolic enzymes or drug transporters
What kind of an effect will a polymorphism that effects pharmacodynamics have?
Altered drug binding or response
What is an indirect effect of a polymorphism?
asdf
What genes encode proteins that will alter metabolic enzymes i.e. pharmacokinetics?
CYP2D6 CYP2C19 CYP2C9 DPD TPMT
What gene encodes for a drug transporter that will alter pharmacokinetics?
SLCO1B1
What drugs will have altered metabolism because of CYP2D6 polymorphisms?
Tamoxifen
Codeine
Paroxetine
What are the different phenotypes of CYP2D6 polymorphisms?
1) Ultrametabolizers
2) Extensive metabolizers
3) Intermediate metabolizers
4) Poor metabolizers
What is the role of CYP2D6 in Tamoxifen therapy?
- Remember Tamoxifen tx. for ER+ breast cancer*
- Tamoxifen requires CYP2D6 to be activated into various active metabolites
- Thus, PM will have less survival of ER+ breast cancer
- UM and EM have better outcomes
What is the role of CYP2D6 in Codiene therapy?
- Codiene is a prodrug*
- PM= inadequate analgesia
- UM= excessive side effects
Should you prescribe codiene to CYP2D6 PM and UM?
NO
What is the role of CYP2D6 in Paroxitene therapy?
- Paroxitene is a SSRI metabolism by CYP2D6
- PM= increased plasma levels–>side effects
- UM= lack of efficacy
What drugs are closely related to polymorphisms in CYP2C19?
Clopidogrel
Omeprazole
What is the role of CYP2C19 in Clopidogrel therapy?
- Clopiogrel is a prodrug
- PM= do not activate drug and do not achieve anticoagulation
- UM= overactivate drug
**Don’t prescribe to PM
What is the role of CYP2C19 in omeprazole therapy?
- Omeprazole is metabolized by CYP2C19
- UM= clear drug too fast–>decreased serum concentrations
- PM= increased plasma concentrations
*****PM have better ulcer cure rates
The activity of what drug is closely related to CYP2C9 polymorphisms?
Warfarin
What is the role of CYP2C9 in Warfarin therapy?
- Warfarin inhibits VKOR
- CYP2C9 metabolizes warfarin
- Reduced function CYP2C9= increased serum warfarin concentration and potential bleeding events
What is the role of VKOR in Warfarin therapy?
VKOR= Vitamin K EpOxide Reductase
- Enzyme that Warfarin acts on VKOR
- Reduced VKOR activity= intrinsically increased Warfarin potency
What type of effect is seen with VKOR polymorphisms?
PHARMACODYNAIMC
In a patient with reduced VKOR and CYP2C9 activity, how would you dose warfarin?
Give a low dose
Polymorphism in SCLO1B1 effects what drug?
Simvastatin
What is the active form of 5-FU?
5dUMP
What is the MOA of 5dUMP?
Inhibits thymidylate synthase
What enzyme inactivates 5-FU?
DDP
For patients with DDP polymorphism (nonfunctional) what is the adverse effect associated with 5-FU adminstration?
Severe myelosuppression
What gene codes for thymidylate synthetase?
TYMS
What type of effect is a polymorphism in TYMS going to have, pharmacokinetic or pharmacodynamic?
PHARMACODYNAMIC
What is the role of a nonfunctional polymorphism in TYMS?
These patients will respond WELL to 5-FU b/c of intrinsically decreased target levels
What enzyme inactivates 6-MP?
TPMT
What is the role of TPMT polymorphisms in 6-MP therapy?
- Nonfunctional TPMT polymorphisms= increased risk for myelosuppression
- Overactivated TPMT= decreased drug efficacy
What is the role of SCLO1B1 in Simvastatin therapy?
- SCLO1B1 is a DRUG TRANSPORTER for SIMVISTATIN
- Transports simvistatin INTO the liver
What is the phenotype of the T/T genotype of SCLO1B1? T/C? C/C?
T/T= normal T/C= decreased C/C= low
What is the functional outcome of a C/C genotype in simvistatin therapy?
INCREASED risk for statin-induced MYOPATHY
What drugs are associated with polymorophisms in ERa genes?
Estrogen and progesterone
*This is an estrogen receptor polymorphism
What is the role of ERa in estrogen therapy?
Polymorphism showed increased HDL levels with HRT
What drug is associated with ADRB2 polymorphisms?
Albuterol
What is the role of ADRB2 in albuterol therapy?
Nonfunctional alleles showed reduced efficacy of albuterol therapy
What is the role of 2nd-hand smoke in ADRB2 polymorphisms and albuterol therapy?
asdf
What indirect pharmacogenetic phenotype is associated with increased risk of venous thromboembolism with oral contraceptive use?
Factor V and prothrombin
What adverse effect is seen with Abacavir?
Hypersensitivity
Steven Johnson’s Syndrome
What gene polymorphism is associated with hypersensitivity reactions to Abacavir? What type of effect is associated with this polymorphism?
HLA-B–> indirect effect
What is interferon-a a common treatment for?
HVC
What polymorphism is associated with poor response to Interferon-a?
IL-28 polymorphisms
Note that this is an indirect effect
