71 - Pharmacogenomics II Flashcards
Define pharmacogenetics
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.
Define pharmacogenomics
The study of how all of the genes (the genome) can
influence responses to drugs
Describe the statistics of drug prescribing in the US
- ~1200 drugs approved in US
- Many drugs have a response rate of between 25%-70%.
- Most drugs are administered on a trial-and-error basis.
- ~15% associated with serious adverse drug reactions (SADRs)
- 75% to 80% caused by predictable non-immunological events
- Study in mid-1990s suggest that 100,000 deaths per year from SADRs
Describe what percent of the population can be resistant to certain drugs
Hypertension Heart failure Antidepressants Cholesterol Asthma
What are the potential advantages of a pharmacogenetic or genomic approach?
- Appropriate patient selection
- Identify patient risk for adverse events
- Optimization of drug dosing
- Increase efficiency of drug development of clinical trials
What is a monogenic drug response?
Variation in a single gene causing difference in specific drug response
What is a multienic drug response?
Variations in multiple genes causing difference in a specific drug response
What is the role of the environment and genes in pharmacological responses?
Drug response is a complex interplay between environmental and genetic factors
Describe the role of gut pharmacobiomics in pharmacological response
- Chemicals compete for the same enzymes as the bacteria
- Contributes to how a patient will respond to the medication
(not in handout, didn’t emphasize)
Describe the genetic variation in the human genome
- Human genome
~3 billion nucleotides
~25,000 genes - Any two people on average differ by one nucleotide in every 1000 in their genome
- Interindividual variation ~3-10 million nucleotides
What is a mutation?
Mutation: Difference in DNA code that occurs in less than 1% of the population
When it is called a mutation, it needs to be rare - less than 1% of the population
What is a polymorphism?
Polymorphisms: Difference in DNA code that occurs in more than 1% of the population
They are not rare, so it is not considered a mutant
Describe gene alleles
- Allele: one of a number of alternate forms of a gene
- An individual usually has only two copies (alleles) of a gene (maternal and paternal)
- Thus, an individual has 2 alleles of a gene
- However, within the population, there can be many alleles of a particular gene
What is a single nucleotide polymorphism?
A single nocleotide change in an amino acid coding chain
What are the two types of SNPs in protein coding regions?
- Synonymous SNPs
- Non-synonymous SNPs
Describe a synoymous SNP
- 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
Describe a nonsynonymous 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
Describe the relevance of a noncoding SNP
- Most SNPs in human genome are found in regions of DNA that are non-protein coding regions (enhancer, promoter, introns)
- Often times no functional change
What CNA noncoding SNPs change?
- Transcription factor binding
- Splicing
- Transcript stability
- Enhancer function
What are insertions and deletions?
Addition or loss of genetic material
What can insertions and deletions lead to?
Can lead to frameshift (a change in which the DNA is read)
- Change in the amino acid sequence of a protein
- Introduction of a stop codon
Can also alter promoter or enhancer and result in an increase transcript quantity
What are copy number variations?
CNVs
- CNVs refer to either complete deletion or duplication of a particular gene
- Gain of function or loss of function
Describe the diversity of polymorphisms in the population
Different ethnic groups will have different polymorphisms
What are cosmopolitan polymorphisms?
Cosmopolitan polymorphisms: polymorphisms common across all ethnic groups
What are population polymorphisms?
Population polymorphisms: polymorphisms that differ between groups (ethnic or race)
What is the phenotype-to-genotype approach to pharmacogenetics?
Start out by directly measuring pharmacogenetic trait (e.g., the effect of warfarin on blood coagulation)
What is a pharmacogenetic trait used for the phenotype-to-genotype approach? What are some examples?
Any measurable trait associated with a drug
a. enzyme activity
b. drug levels in bodily fluids
c. drug metabolite in bodily fluids
d. physiological response (blood pressure
What are the benefits and disadvantages of using the phenotype-to-genotype approach?
Beneficial because sum of all genes giving rise to an effect
Disadvantages: non-genetic influences giving rise to and unstable responses
Describe the process of using the phenotype-to-genotype approach
- Start out by directly measuring pharmacogenetic trait (e.g., the effect of warfarin on blood coagulation)
- Group outliers and normal responders
- Genotype individuals from each group to determine differences in DNA sequence, either using the candidate gene approach or the genome wide approach
Describe the cantidate gene approach of the phenotype-to-genotype method?
- Determine polymorphisms by genotyping a specific gene that is predicted to cause differences in pharmacogenetic trait between the two groups
- Requires knowledge of cellular mechanism
- Disadvantage is that wrong gene might be studied
Describe the genome-wide approach of the phenotype-to-genotype method?
- Does not require knowledge of cellular mechanism responsible for trait
- Unbiased survey of all difference in entire genome between two groups
- Disadvantage is identification that does not matter
