Pharmacogenomics Flashcards
Pharmacogenetics
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
Pharmacogenomics
study of how all of the genes (the genome) can
influence responses to drugs
Monogenic drug response
Variation in a single gene causing difference in specific drug response
Multigenic drug response
Variations in multiple genes causing difference in a specific drug response
Gene by environment phenotype
Drug response is a complex interplay between environmental and genetic factors
Mutation
Difference in DNA code that occurs in less than 1% of the population
Polymorphism
Difference in DNA code that occurs in more than 1% of the population
Allele
one of a number of alternate forms of a gene
SNP =
single nucleotide change in protein coding region
Synonymous SNP
NUCLEOTIDE CHANGE DOES NOT CAUSE AMINO ACID SUBSTITUTION
Non-synonymous SNP
LEADS TO AN AMINO ACID SUBSTITUTION
Indel
insertions/deletions
addition or loss of genetic material
can lead to frameshift - change AA or insert stop codon
alter promoter or enhancer - can increase transcription quantity
Most SNP’s are found
in regions that are NON-PROTEIN CODING REGIONS (enhancers, promoters, introns)
Copy number variation (CNV)
either complete deletion or duplication of a particular gene
gain or loss of function results
Cosmopolitan polymorphisms
polymorphisms common across all ethnic groups
Population polymorphisms
polymorphisms that differ between groups (ethnic or race)
Phenotype to genotype approach
start out BY DIRECTLY MEASURING PHARMACOGENETIC TRAIT
Pharmacogenetic trait
any measurable trait associated with DRUG ENZYME ACTIVITY, DRUG LEVELS IN BODY, DRUG METABOLITE IN BODY FLUIDS, PHYSIOLOGIC RESPONSE
Candidate gene approach
determine polymorphisms by genotyping specific gene predicted to cause differences in pharmacogenetic trait between two groups
REQUIRES KNOWLEDGE OF CELLULAR MECHANISM
WRONG GENE MIGHT BE STUDIED
Genome wide approach
DOES NOT REQUIRE KNOWLEDGE OF CELLULAR MECHANISM RESPONSIBLE FOR TRAIT
UNBIASED SURVEY OF ALL DIFFERENCE IN ENTIRE GENOME BETWEEN TWO GROUPS
identification that does not matter is disadvantage
Three types of genome wide approach
sanger sequencing
SNP microarrays
Next generation sequencing
4 polymorphisms of CYP2D6
ultra metabolizers
extensive metabolizers
intermediate metabolizers
poor metabolizers
CYP2D6 metabolism (3 drugs) (pharmacodynamic or pharmacokinetic?)
tamoxifen
codeine
paroxetine
all three pharmacokinetic
CYP2C19 metabolism (3 drugs)
Clopidogrel
Omeprazole
Lansoprazole
CYP2C19 levels of metabolism (3)
normal
intermediate
poor
CYP2C9 drug
Reduced function alleles?
warfarin
CYP2C92, CYP2C93 – metabolize slower, lower dose requirements
Pharmacokinetic polymorphism of warfarin?
Pharmacodynamic polymorphism of warfarin?
CYP2C9
VKORC1
VKORC1 SNP with lowest activity?
VKORC1-AA
Polymorphisms affecting cancer treatment (2 drugs)
5-FU - DPD and TYMS enzymes
6-MP - TPMT enzyme
Role of DPD with 5-FU (pharmacodynamic or pharmacokinetic?)
Role of TYMS with 5-FU(pharmacodynamic or pharmacokinetic?)
DPD inactivates 5-FU, REDUCES TOXICITY - DECREASED FUNCTION LEADS TO INCREASED TOXICITY (pharmacokinetic)
TYMS is inhibited by 5-FU normally - CAN HAVE INCREASED OR DECREASED ACITIVTY (pharmacodynamic)
Role of TPMT with 6-MP
normally INACTIVATES 6-MP
SLCO1B1 and Simvastatin (3 levels of function)
what chromosome?
(pharmacodynamic or pharmacokinetic?)
normal transport (T/T genotype) decreased transport (T/C genotype) low transport (C/C genotype)
chromosome 12 highly associated
pharmacokinetic
Estrogen receptor polymorphism
pharmacodynamic or pharmacokinetic?
intron between 1st and 2nd exon of ER-alpha gene
homozygotes for less common allele had GREATER INCREASE IN HDL LEVELS FOLLOWING HRT
pharmacodynamic
ADRB2 phenotype and albuterol use
pharmacodynamic or pharmacokinetic?
ARG/ARG HOMOZYGOTES
DECREASED PEF WITH ALBUTEROL ADMINISTRATION
passive smoking augments down-regulatory effect
pharmacodynamic
Indirect pharmacogenetic drug associations (4 drugs)
oral contraceptives
abacavir
APO-E and alzheimer’s drug therapy
interferon-alpha and Hep C
Polymorphisms in what affect venous thromboembolism with oral contraceptives?
factor V and Prothrombin
Abacavir phenotype
result?
HLA-B*57:01
HIGH RISK OF HYPERSENSITIVTY REACTION
Apo-E phenotype
result?
ABSENCE OF CERTAIN ALLELES
better therapeutic success for therapy with tacrine in alzheimer’s disease
SNP polymorphism associated with IFN-alpha effectiveness
IL-28B
CC - favorable response genotype
CT or TT - unfavorable response genotype
