Pharmacogenomics + Pharmacogenetics Flashcards
CYP2D6
Pharmacogenetic phenotype- PHARMACOKINETIC
-enzyme that metabolizes about 25% of all meds
CYP2C9
Pharmacogenetic phenotype- PHARMACOKINETIC
-metabolism of many drugs - ESP KNOWN FOR METABOLISM OF WARFARIN
-some people are poor metabolizers=hgih warfarin levels = bleeding complications
CYP2C19
Pharmacogenetic phenotype- PHARMACOKINETIC
- chinese and japanese have this = greater cure rate bc more activity of the drugs
- proton pump inh inactivators (omeprazole and iansoproazole)
TYMS
- pharmacogenetic phenotype - RECEPTOR/TARGET:
- thymidylate synthetase
- methotrexate - anticancer or immunosuppressive inh methionine and DNA synthesis
- indel occurs where promoter enhanced for TYMS = inc breakdown of methotrexate = dec efficacy and poorer prognosis
ERalpha
- pharmacogenetic phenotype - RECEPTOR/TARGET: ESTROGEN RECEPTOR alpha
- polymorphism in the intron between the 1st and 2nd exon of the ERalpha gene
- homozygotes for the less common (c/c) allele had a greater inc in HDL levels following HRT
APOE
- pharmacogenetic phenotype- INDIRECT: Apolipoprotein E
- lipoprotein found in chylomicrons VLDL, IDL, and HDL
- absence of certain allelesin the APOE gene corelate with better than therapeutic success for alzheimers disease therapy with tacrine
KCNE2
- pharmacogenetic phenotype- INDIRECT: Potassium channel sub-unit
- 1.6% of population are variants
- antibiotic therapy (clarythromycin) can induce prolonged QT interval
- result in a deadly cardiac arrhythmia
OCT1
-hepatic transporter that mediates the uptake of organic cations
pharmacogenetics definition:
study of the genetic basis for variations in drug response
pharmacogenomics definition:
uses tools for surveying the entire genome to assess multigenetic determinants of a drug response
gene by environment phenotype definition:
complex interplay between environmental and genetic factors
monogenic response v multigenic response:
expression of a single gene yields single phenotype
vs
networks of genes acting together to create a single phenotype
recessive trait
phenotype exhibited when a non-functional allele occurs on both the maternal and paternal chromosome
dominant trait
phenotype exhibited when a non-functional allele occurs on either the maternal or paternal chromosome
co-dominant trait
heterozygotes display an intermediate phenotype as compared to wild type and homozygotes
polymorphism definition
variation in the genetic code present at an allele frequency of >=1%
-ex = SNPs
single nucleotide polymorphism (SNP)
-genetic consequence:
1) if in coding region:
a) nonsynonymous/missense
- BP change–> single amino acid change (different amino acid!)
- change in protein structure, stability, substrate affinity, intro of stop codon
b) synonymous/sense
- BP change= NO amino acid substitution (still get same amino acid)
- result in dec transcript stability or alter splicing
2) non-coding region:
- promoter
- intron
- reg region
- Results:
- -> transcription factor binding change
- -> enhancer change
- -> splicing change
- -> transcript stability change
Indels:
- insteritions = frameshift (change is structure, alter promoter =inc transcript quality, gene dup/mult, stop codon)
- deletions =loss of genetic material (loss of gene; premature stop codon)
cosmopolitan polymorphisms:
polymorph common across all ethnic groups
population polymorphism:
polymorph that differ between groups (ethnic or race)
phenotype to genotype measuring:
drug response outliers are compared to normal responders to identify altered responses to drugs
OUTCOME (PHENOTYPE) AND THEN YOU GO LOOKING FOR WHATS DIFFERENT (GENOTYPE)
measure a pharmacogenetic trait:
TRAIT IS NOT THE GENETIC SEQUENCE - ITS THE MEASURABLE RESPONSE TO THE DRUG!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!*** IT IS SOMETHING THAT CAN CHANGE!!!! CANT CHANGE THE GENETIC SEQUENCE SO IT IS NOT A TRAIT!
CAN I CHANGE IT WITH DRUG??=
- enzyme activity
- drug levels in bodily fluids
- drug metabolite in bodily fluids
- physiological response (BP)
- gene expression patterns
Adv/Disadv of pharmacogenetic traits:
- adv=sum of all genes giving rise to an effect (LOOKING AT FINAL ENDPOINT)
- disadv=non-genetic influences giving rise to and unstable result (CANT FACTOR DIET OR OTHER DISEASE)
Genotype to phenotype definition:
genome is surveyed to determine if genomic variability results in phenotypic variability
genotyping:
- testing that reveals the specific genetic sequence of an allele
- requires extraction of the DNA from somatic cells (blood or buccal)
adv/disadv of genotyping:
1) adv=
- DNA is stable
- testing needs to be done only once
2) disadv=
- dependent upon annealing (TAGGING) of an oligonucleotide sequence to DNA
- false pos/neg
candidate gene approach:
candiadte gene:
- known or partially known cellular pathway involved in a drug response
- identify polymorphisms which result in a response (patient screening, data base)
- test the polymorphism in a function assay
Disadv to candidate gene approarch?
-wrong gene may be studied
genome wide approach:
- unbiased survery of the genome
- compare DNA, RNA, or protein of identically treated patients (those with adverse drug reaction vs normal responders)
disadv to genome wide approach:
-id of a variation that does not matter
Pharmacogenetic phenotype- PHARMACOKINETIC:
- polymorphism in a gene or genes that regulate pharmacokinetics
- enzymes or transporters
- alter drug concentrations resulting in changes in therapeutic and adverse events
P450s, OCT1, CYP2D6, CYP2C9 … other metabolism enzymes
pharmacogenetic phenotype - RECEPTOR/TARGET:
- polymorphism in a gene that codes for drug target
- alters drug response (impaired drug binding for example)
CHANGE IN DRUG BINDING AFFINITY TO TARGET
ex- TYMS, ERalpha
pharmacogenetic phenotype- INDIRECT:
-polymorphism in a gene that does not interact with the drug, is not a direct target of the drug, or is not involved with the drugs disposition
Ex: APOE, KCNE2
Major types of evidence?
- screens of tissue from mult patients linking a polymorphism to a trait
- preclinical functional studies
- clinical phenotype/genotype studies
Results of pharmacogenomic data can lead to:
- id of new drug targets
- genomic-specific development of new drugs
- genotype-specific dosing regimens
