Lecture 1 - Pharmacogenomics Flashcards
Pharmacogenetics
the study of sequence variation (single nucleotide polymorphism - SNPs) in individual genes, and the role sequence variation plays in determining an individual’s metabolism of drugs (pharmacokinetic) and response to drugs (pharmacodynamic)
Pharmacokinetic vs pharmacodynamic
kinetic: metabolism of drugs
dynamic: response to drugs
Which group has the lowest alcohol abuse rate and why?
asians d/t inactive allele (SNP) of acetaldehyde dehydrogenase (genetic disulfiram)
this causes flushing (asian glow) and N/V/HA, hypotension
Where is the bulk of acetalydehyde dehydrogenase activity in the body?
ALDH2 in the mitochondria (vs ALDH1 found in cytosol)
Of individuals that abuse alcohol, which group is more likely to develop esophageal cancer?
asians
Since there is no ALDH there is a build up of acid aldehyde which modifies DNA
What is a SNP?
a DNA sequence variation that occurs when a single nucleotide (A, T, C, or G) in the genome differs between two individuals
SNPs make up about ~80% of all human variation
for it to be considered and not a SNP, it must occur in at least 1% of the population
Where are the most SNPs found?
integrenic region –between region genes –impact on phenotype
What are the different locations of SNPs are found?
protein coding region of genes, exon-intron boundaries of genes, tandem repeats in promoter regions, and intergenic regions
coding regions, exon-intron boundaries, promoter regions can predispose individual to disease, or influence response to drug
Synonymous vs non-synonymous SNPs?
synonymous = least interesting, no change to amino acid
non-synonymous (both missense/nonsense) change amino acid
Monogenic vs polygenic trait
monogenic trait (classic mendelian inheritance) -bimodal/trimodal distribution
polygenic trait (quantitative) -unimodal distribution with wide distribution d/t gene- environment interactions
the general population looks like F2
How does pharmacogenetics play a role in drug companies?
Phenotype driven or “forward genetics”
When drug companies are testing drugs, they plot adverse reactions on a graph, bimodal distribution means its a monogenic trait so they begin to do family studies to look for the gene responsible for the adverse drug reactions –typically its d/t enzyme responsible for metabolizing the drug
Nanosphere test
tests which pts will have adverse reactions to warfarin based on VKORC1 and CYP2C9 alleles
FDA approved before starting Warfarin
will determine dosing of warfarin
Most responses to drugs, and certainly most disease, are ___monogenic or polygenic?
polygenic (2 or more polymorphic genes)
What are the different classes of SNPs and their effects on drugs?
pharmacokinetics:
- drug metabolizing enzymes
- drug transporters
pharmacodynamics:
- target proteins
What are the examples of drugs involved in pharmacogenetics?
EtOH
Pheytoin
Warfarin
5-FU
Phenytoin
response to dictated by polymorphisms in all 3 classes (metabolizing, transporters, target)
1) SNP in CYP2C9, CYP2C19 (increase serum levels –> ADRs)
2) SNP in MDR1 gene promoter (poor therapeutic response)
3) SNP in voltage gated Na+ (poor therapeutic response)
Warfarin
the second most common ER visit related to ADRs (behind insulin)
30% of pts are at higher risk for bleeding d/t excessive levels of warfarin in blood
activated in liver by CYP2C9
VKORK1
warfarin inhibits this to stop activation of vitamin K
5-FU
dihydropyrmidine dehydrogenase (DPD) --polymorphic Thymidylate synthase (TS) - polymorphic
DPD found in the liver to inactivate 5-FU –> can lead to increased 5FU which can lead to myelopsuppression
TS:
2 tandem repeat –> decrease TS –> good for the drug drug
3 tandem repeat –> increase TS –> bad for the drug
CYP2D6
most important P450 enzyme
~50% of ADRs are d/t polymorphic CYP2D6
decrease action:
1) needed for metabolism (increase serum levels)
2) prodrug –> needed for activation (non-responsive)
amplification:
1) inactivation too rapid (non-responsive)
2) prodrug activation too rapid (increase risk of ADRs, increased serum levels)
Codeine
2 inactive forms of CYP2D6: poor metabolizer –give alternative opioid such as hydrocodone or oxycodone
1 inactive YP2D6 (ultra-metabolizer) –risk of respiratory depression
Pharmacogenomics
looks at ALL sequenced variance
-studies include environment- gene interactions
