Pharmacogenetics Flashcards
Pharmacogenetics
Evaluates how an individual’s genetic makeup corresponds to their response to a particular medication
Looks at specific allele differences within a single gene
Pharmacogenomics
Combines pharmacogenetics with genomic studies
Uses large groups of patients to evaluate how candidate drugs interact with a range of genes and their protein products
Examines the entire genome for allele differences
No target known
Identified SNP may have direct link to phenotyp
Require large genome wide association studies
Goals for personalized medicine
Identify genetic differences between people that affect drug response
Develop genetic tests that predict an individual’s response to a drug
Tailor medical treatments to the individual
Ultra drug metabolizers vs Poor drug metabolizers for
- Drugs
- Pro-drugs
- UM: inactivation of the drug, PM: toxic doses
2. UM: active form/toxic doses, PM: little conversion/ineffective
3 main consequences of genetic polymorphisms
- None (outside of coding and regulatory regions, synonymous substitution, no impact on function of protein)
- Decrease or loss of function of the encoded protein
- Increase in function of the encoded protein
4 results of a decrease in function mutation
Less enzyme may be produced (decreased regulation)
Enzyme may not be complete (stop codon insertion)
Enzyme may not be as stable
Less binding affinity to substrate
3 results of a increase in function mutation
More production (regulation or genomic copies)
More stable
More binding affinity
Tuberculosis
An infectious disease caused by Mycobacterium tuberculosis
Typically attacks the lungs, but can affect other parts of the body
Airborne disease
What drug is used to treat tuberculosis?
Isoniazid
Isoniazid
Used to treat TB
Metabolized in the liver via acetylation and then cleared from the body
High incidence of peripheral neuropathy caused by the drug reaching toxic levels
What enzyme acetylates isoniazid?
N-Acetyl-Transferase
NAT2
NAT2 gene
Has several alleles which cause variation in the rate of acetylation of various drugs including isoniazid
NAT2
- Rapid acetylator
- Slow acetylator
- Wild type, dominant allele
2. Various amino acid substitution in NAT2 lead to reduced efficiency of gene, recessive
Thiopurines are used to treat…
Acute lymphoblastic leukemia
Inflammatory bowel disease
Prevent organ rejection after transplantation
Other autoimmune diseases
Thiopurine methyltransferase (TPMT)
An enzyme that allows methylation of thiopurines
Thiopurines are converted into thioguanine nucleotides and get inserted into DNA bases and can have toxic effects within the cell at high levels
Reduced TPMT activity can lead to fatal toxicity
TMPT Clinical relevance
Patients with 2 nonfunctional variant alleles are given 6-10% of the standard dose of thiopurines
Heterozygous patients can be started on full dose but must be closely monitored to avoid toxicity
Consequences if you have no CYP2D6 enzymes
Poor drug metabolizers Too slow drug metabolism Too high drug levels at ordinary dose High risk for adverse drug results No response from certain prodrugs
Consequences if you have CYP2D6 gene duplications
Ultra rapid drug metabolizers
No drug response at ordinary dosage
Nortriptyline
Used to treat major depression
Inhibits the reuptake of norepinephrine and to a lesser extent serotonin
Has a narrow therapeutic index (therapeutic dose is close to toxic dose)
Side effects of nortriptyline in a poor drug metabolizer
Mild: drowsiness, dry mouth, nausea, headache
Serious: seizures, cardiac rhythm disturbances
Tamoxifen
Used for the treatment of ER+ breast cancer
Prodrug
Metabolized by CYP2D6 to its active metabolites 4-hydroxytamoxifen and endoxifen
What is the result in function for the following CYP2D6 allele frequencies?
- *2xN
- *10
- *17
- *4
- *5
- increased function
- decreased function
- decreased function
- no function
- no function
Plavix
Used to treat blood clots
Prodrug is metabolized by CYP2C19 to active form
Some alleles result in a poor metabolizer resulting in an inactive drug
3 requirements for pharmacogenetics to work
Knowledge of target genes ahead of time
Direct link between SNP and phenotype
Require fairly small sample sizes to identify
How to detect SNPs
Isolate DNA
Digest DNA into ‘bite sizes’ chunks
Label DNA with a fluorescent probe
Hybridize onto a matrix containing an array of oligonucleotides representing known SNPs
Detect signal for each SNP spot on the array
Treatment for Hep C
Interferon combined with ribavirin
