Pharmacogenomics Flashcards
What are pharmacogenetics?
Study of the genetic basis for variations in drug response. Typically used to define the study of how variation in single genes influence the response to a single drug
What are pharmacogenomics?
The study of how all of the genes (the genome) can influence responses to drugs
What is the usual response rate to drugs?
25-70%
What are the four clinical applications of pharmacogenetics/genomics?
- Appropriate pt selection
- Identify pt risk
- Optimization of drug dosing
- Increase efficiency of drug development
How does pharmacogenetics lead to increased efficiency of drug development trials?
Can select out people who would have a response.
What is a monogenic drug response?
Variation in a single gene causing difference in specific drug response
What is a multigenic drug response?
Variations in multiple gene causing difference in a specific drug response
What is gut pharmacol microbiomes?
Changes in drugs from bacteria can change its effects
What is the 5’ protective bit of DNA? 3’?
5’ cap.
Poly-A 3’ tail
What is removed during splicing?
Introns removed.
Exons Expressed
What is the function of eukaryotic RNA pol I-III?
I =***
II =
III =
True or false: genetic variations in the introns can affect expression
True
What is a mutation as compared to a polymorphism?
Mutation = DNA code change in less than 1% of the population
Polymorphism = DNA code change in MORE than 1% of the population
What is an allele?
One number of alternate forms of a gene
An individual usually has how many alleles?
two (maternal and paternal)
What are single nucleotide polymorphisms?
Single nucleotide change in an allele
What is a synonymous SNP? What is the significance of this?
When the base pair does NOT cause an amino acid substitution.
may result in change in transcript stability, leading to increased or decreased protein expression
What is a nonsynonymous SNP? What is the significance of this?
Base pair changes that lead to an amino acid substitution
May change protein structure, stability, substrate affinity.
How can synonymous SNPs lead to changes in the protein expression?
Alternate splicing products, variable stability of the DNA
How can noncoding SNPs alter DNA? (4)
Alter:
- Transcription factor binding
- Splicing
- Transcript stability
- Enhancer functions
What are frameshift mutations?
Insertions/deletions that lead to changes in everything downstream of the nucleotide change
What are copy number variations? What can these result in?
When an entire gene is duplicated or deleted
Can result in gain or loss of function
What are cosmopolitan polymorphisms?
Polymorphisms common across all ethnic groups
What are population polymorphisms?
Polymorphisms that differ between groups (ethnic or race)
What CYP enzyme polymorphism is only found in the japanese?
CYP2C18
What is the phenotype-to-genotype approach?
Start out by directly measuring pharmacogenetic trait (e.g. effect of warfarin on blood coagulation)
What is a pharmacogenetic trait?
Any measurable trait associated with a drug (e.g. enzyme activity, drug levels in bodily fluids etc)
What are the major advantages and disadvantages of the phenotype-to-genotype approach?
benefit = sum of all genes giving rise to an effect
Disadvantage = Miss non-genetic influences
What are the steps of phenotype-to-genotype approach?
See the effect of a drug, then group people accordingly and genotype them
What is the candidate gene approach?
Determine polymorphisms by genotyping a specific gene that is predicted to cause difference in pharmacogenetic trait between the two groups
What is the genome-wide approach?
Unbiased survey of all difference in entire genome between two groups
What are the three major genome sequencing techniques?
Sanger
SNP microarrays
Next gen
What are the steps of the Sanger sequence?
Primer and DNA polymerases along with fluorinated ddNTPs, which cause termination of the growing nucleotide
What is the gold standard for DNA sequencing?
Sanger
How do the SNP microarrays work?
ssDNA fragments used where there are known to be SNPs. Fragmented sample spotted onto a plate with different SNP allele.
Different color wavelengths correspond to different allele combinations
What is involved in next-gen sequencing?
Isolated genomic fragments, that are adhered to plates/beads. Heights can be measured in order to determine sequence
