Pharmacogenetics/Pharmcogenomics Flashcards
(63 cards)
The study of the genetic basis for variations in drug
response. Typical used to define the study of how variation in single gene
influences the response to a single drug.
Pharmcogenetics
The study of how all of the genes (the genome) can
influence responses to drugs.
Pharmcogenomics
Variation in a single gene causing difference in specific drug response
monogenic drug response
Variations in multiple genes causing difference in a specific drug response
Multigenic drug response
Drug response is a complex interplay between environmental and genetic factors
gene-by-environment phenotype
role of the gut microbiome in pharmacological responses
Pharmacomicrobiomics
explain how microbes can affect pharamcomicrobiomics
Activate or inactive drugs
Generate toxic byproducts of drugs
Alter drug metabolism (direct and indirect)
E.g. enterohepatic cycling
- Irinotecan is cleared by being glucuronidated in liver, excreted into intestine, and removed in feces
- Some microbes living in intestines produce beta-glucuronidase
- Reactivates irinotecan and causes toxicity (severe diarrhea)
Difference in DNA code that occurs in MORE THAN 1% of the population
Polymorphisms
Difference in DNA code that occurs in LESS THAN 1% of the population
mutation
Base pair change does not cause amino acid substitution
- May result in decreased transcript stability or alter splicing
- This can lead to changes in protein expression and/or function
Synonymous SNP
Base pair change leads to an amino acid substitution
- May result in change in protein structure, stability, substrate affinity, introduction of a stop codon
Nonsynonymous SNP
Most SNPs in human genome are found in regions of DNA that are _____
non-protein coding regions (enhancer, promoter, introns)
For noncoding SNPs there’s often no functional change
However can alter what?
Transcription factor binding
Splicing
Transcript stability
Enhancer function
Insertions/deletions (Indels):
Can lead to 1
- change in 2 of a protein
- introduction of a 3
Alter promoter or enhance and result in an increase 4
- frameshift
- AA sequence
- stop codon
- transcript quantity
___ refer to either complete deletion or duplication of a particular gene
Gain of function or loss of function
Copy number variations (CNV)
polymorphisms common across all ethnic groups
Cosmopolitan polymorphisms
polymorphisms that differ between groups (ethnic or race)
population polymorphisms
Phenotype-to-genotype approach
A. Start out by directly measuring 1 (e.g., the effect of warfarin on blood coagulation)
B. Group 2 and outliers
C. 3 individuals from each group to determine if polymorphisms account for phenotype groups
- pharmcogenetic trait
- normal responders
- Genotype
Pharmacogenetic trait: Any measurable trait associated with a drug
a. 1 activity
b. drug levels in 2
c. drug 3 in bodily fluids
d. 4 response (blood pressure)
- enzyme
- bodily fluids
- metabolites
- physiological
gene approach versus genome-wide approach
A. Determine polymorphisms by genotyping a SPECIFIC gene that is predicted to cause differences in pharmacogenetic trait between the two groups
B. Unbiased survey of ALL difference in ENTIRE genome between two groups
A = Candidate gene approach
B = Genome-wide approach
gene approach versus genome-wide approach
A. Does not require knowledge of cellular mechanism responsible for trait
B. Requires knowledge of cellular mechanism to choose gene to study
A = genome-wide approach
B = candidate gene approach
Disadvantage of candidate gene approach
wrong gene might be studied
disadvantage of genome-wide approach
identification of genetic differences that do not effect drug response
The effect of a polymorphism in a gene that codes for drug targets such as receptors or enzymes
Can impair or enhance drug binding
Alters drug response
pharmacodynamics, indirect or pharmcokinetics?
pharmacodynamics
