Pharmacogenomics Flashcards
Definition of Pharmacogenetics?
Study of sequence variation in individual genes and ther role that plays in determining and individual’s metabolism and response to drugs
what racial group has the lowest rate of alcohol abuse?
Asians
Why do Asians have a lower rate of alcohol abuse?
Becasue they are more likely to have a genetic makeup that produces less acetylaldehyde dehydrogenase, which leads to accumulation of acetaldehyde and the “Asian flush” (and nausea, vomiting, headache, hypotension)
What is the specific variant in acetaldehyde deydrogenase gene that Asians are more likely to have which acts like a “genetic Disulfram”
ALDH2*2
Which racial group is more likely to develop esophogeal cancer?
Asians
how many protein coding genes are there in the human genome?
20-25k
what is the estimated identity of nucelotide sequences between any two individuals?
99.5-99.9%
what is the source of the greatest variability in human genetic variation?
single nucleotide polymorphisms (SNPs)
these make up about 80% of all genetic variation
what is the definition of an SNP?
a variation in a single nucleotide in a gene that occurs in at least 1% of the population
(less and it is a mutation)
how many SNPs are estimated to exist in the human genome?
10-30 million
(approximately 10% in humans have more than 2 possible alleles)
2/3 SNPs involve the replacement of cytosine for what?
thymine
what is a nonsense mutation?
mutation that results in a change from a coding amino acid to a stop codon
what might be the significant of a SNP in a non-coding sequence (i.e., promoter region)?
cound get a promoter sequence that increases gene transcription of the downstream gene
what happens there are mutations on the ends of introns?
can lead to loss of the exon or inclusion of the intron into the mRNA and therefore, final product
what are the two types of SNP-derived traits?
monogenic (classic Mendelian)
polygenic (continuous variation)
*pentamodal in theory, unimodal in practice
what are the three classes of SNPs that modify patient drug responses?
- metabolize drugs into active or inactive metabolites (e.g., CYPs)
- drug transporters - move drugs between or out of body compartments or cells
- target proteins - bind therapeutic drugs resulting in a change in cell physiology
1 and 2 affect pharmacokinetics
3 affects pharmacodynamics
What affects the amount of phenytoin that reaches the BBB?
MDR1 - multi-drug resistance protein 1
This is polygenic
what happens to phenytoin response if there are SNPs in the voltage-gated Na+ channels?
leads to poor binding affinity and poor therapeutic response
What CYP mutations will increase phenytoin blood levels?
CYP2C9 or 2C19
decreases metabolism, increasing blood levels
(ataxia, confusion, slurred speech, decresed coordination)
What is the mechanism of action of warfarin?
It inhbits VKORC1, which is the enzyme that reduces Vitamin K (making it active)
Which CYP variants are associated with increased bleeding on warfarin?
CYP2C9*2
CYP2C9*3
(*1 is wild-type)
There is a SNP in CYP2C9 that is not tested by Nanosphere. Which one is it?
*8, which is the most common SNP in the African American population
What is 5-FU converted to as the active metabolite?
5-FdUMP
What is the mechanism of action of 5-FU?
Once converted to 5-FdUMP it inhibits thymidylate snynthase, which si required for de novo pyrmidine synthesis, slowing DNA replication
What is one mutation that leads to 5-FU toxicity?
DPD, the enzyme that converts 5-FU into 5-FdUMP, leading to poor metabolism
the drug accumulates causing toxicity and bone marrow suppression in this population
*there is a genotype test for this that should be done prior to starting 5-FU therapy
What is a second mutation that leads to poor treatment response to 5-FU?
Polymorphisms in thymidylate synthase - triple tandem repeats (most common is double tandem repeast) can sometimes lead to reduced responsiveness to 5-FU
*No approved test for this
What percent of ADRs are due to drugs metabolized by CYP2D6?
50%
what should you do for a CYP2D6 poor metabolizer for opiod?
don’t give codeine - prodrug that won’t get converted
give hydrocodone or oxycodone instead
What CYP2D6 alleles do you see causing ADRs in anti-psychotics?
*3,*4,*5 cause poor metabolism and lead to tardive dyskenesia (decrease dose)
ultra-metabolizer - increase dose
What is pharmacogenomics?
study of all variants/polymorphisms that influence a patient’s response to a drug
GINA protections don’t apply where?
life insurance
disability
long-term care insurance market
