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
