Pharmacogenetics Flashcards
Pharmacogenetics
study of genetic basis for variation in drug response
how variation in single genes influences response to single drug
Pharmacogenomics
study of how all genes can influence responses to drugs
Advantages of pharmacogenetics
patient selection
risk/AE
optimization of dosing
increased efficacy
Monogenic drug response
variation in single gene causing differences in specific response
Multigenic gene response
variation in multiple genes causing differences in specific drug response
Pharmacomicrobiomics
microbes activate/inactivate drugs, generate toxic byproducts, alter drug metabolism
Mutation
difference in DNA code that occurs in less than 1% of population
Polymorphism
difference in DNA code that occurs in >1% of population
Synonymous SNP
base pair change does not cause substitution
May result in decreased transcript stability or alter splicing
Causes change in protein expression/function
Non-synonymous SNP
base pair change leads to substitution
Result in change in protein structure, stability, affinity, stop codon
Non-coding SNP
no functional change
alter TF binding, splicing, transcript stability, enhancer function
Insertion/deletion
addition/loss of genetic material; frameshift
change in aa sequence of protein, intro of stop codon, alter promoter/enhancer
Copy number variation
complete deletion/duplication
GOF/LOF
Cosmopolitan polymorphism
common across all ethnic groups
Population polymorphism
polymorphisms differ between groups
Phenotype-to-genotype approach
measurement of pharmacogenetic traits
- measure pharmacogenetic trait
- genotype individuals from each group to determine if polymorphisms account for phenotype groups
Pharmacogenetic trait
any measureable trait associated w/drug
Candidate gene approach
determine polymorphisms by genotyping specific gene predicted to cause differences in pharmacogenetic trait between two groups
Requires knowledge of cellular mechanisms
Disadvantage - wrong gene might be studied
Genome-wide approach
unbiased survey of difference in entire genome between two groups
No cellular mechanism knowledge needed
Disadvantage - identification of genetic difference that do not effect drug response
CYP2D6 and tamoxifen
activated by CYP2D6 - inhibit estrogen receptor
Extensive metabolizers = high efficacy
Poor metabolizers = low efficacy - use aromatase inh
CYP2D6 and Codeine
Extensive metabolizers = excessive side effects
Poor metabolizers = inadequate analgesia
CYP2D6 and SSRI (Paroxetine
Inactivated by CYP2D6
Extensive metabolizers - less Paroxetine
Poor metabolizers - too much Paroxetine
CYP2C19 and Clopidogrel
activated by CYP2C19
Poor metabolizers = might not get effect of drug
Increased risk of death from MI/stroke
CYP2C19 and PPI (omeprazole, lansoprazole)
Inactivated by CYP2C19
Poor metabolizers = higher drug content = higher % of ulcer cure rate
CYP2C19 and warfarin
inactivated by CYP2C19
reduced function alleles CYP2C19 1/2 - slow metabolism = higher risk for bleeds
Require lower dose and longer stabilization
5-FU and DPD
DPD inactivates 5-FU
mut:A polymorphism = non-functional = high 5-FU toxicity
6-MP and TPMT
TPMT inactivates 6-MP
mutant = non-functional = high 6-MP activity
SLC01B1
Liver uptake of simvastatin - lower transport = high myopathy risk
T/T (val/val) = normal transport
T/C (val/ala) = decreased transport
C/C (ala/ala) = low transport
ADRB2
Response to albuterol
Arg/Arg = reduced PEF - avoid albuterol
Gly/Gly = increased PEF - albuterol fine
Pharmacodynamic phenotype
effect of polymorphism in gene that codes for drug targets (enzyme/receptor)
VKORC1 and warfarin
Phenotypes - GG/GA/AA
AA has lowest activity
Less Vitamin K dependent clotting factors produced - lower warfarin dose required for therapeutic effect
5-FU and thymidylate synthetase
mutation = higher TS activity = poor 5-FU effect
Estrogen receptor
homozygotes for less common allele had greater increase of HDL following HRT
Indirect phenotype
effects of polymorphisms do not interact with drug
Factor V/Prothombin risk
increased risk of VTE w/oral contraceptives
HLA-B*57:01 risk
high risk of ABC-HSN
no effects on PKX/PDX of abacavir
APOE
absence of certain alleles = better success in Alzheimer Tacrine therapy
Hep C
SNP polymorphism in IL-28B (CT/TT) = unfavorable response to INFa in Hep C
