71 - Pharmacogenomics II

Question 1

Define pharmacogenetics

Answer 1

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.

Question 2

Define pharmacogenomics

Answer 2

The study of how all of the genes (the genome) can

influence responses to drugs

Question 3

Describe the statistics of drug prescribing in the US

Answer 3

• ~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

Question 4

Describe what percent of the population can be resistant to certain drugs

Answer 4

Hypertension
Heart failure
Antidepressants
Cholesterol 
Asthma

Question 5

What are the potential advantages of a pharmacogenetic or genomic approach?

Answer 5

• Appropriate patient selection
• Identify patient risk for adverse events
• Optimization of drug dosing
• Increase efficiency of drug development of clinical trials

Question 6

What is a monogenic drug response?

Answer 6

Variation in a single gene causing difference in specific drug response

Question 7

What is a multienic drug response?

Answer 7

Variations in multiple genes causing difference in a specific drug response

Question 8

What is the role of the environment and genes in pharmacological responses?

Answer 8

Drug response is a complex interplay between environmental and genetic factors

Question 9

Describe the role of gut pharmacobiomics in pharmacological response

Answer 9

• 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)

Question 10

Describe the genetic variation in the human genome

Answer 10

• 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

Question 11

What is a mutation?

Answer 11

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

Question 12

What is a polymorphism?

Answer 12

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

Question 13

Describe gene alleles

Answer 13

• 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

Question 14

What is a single nucleotide polymorphism?

Answer 14

A single nocleotide change in an amino acid coding chain

Question 15

What are the two types of SNPs in protein coding regions?

Answer 15

• Synonymous SNPs

- Non-synonymous SNPs

Question 16

Describe a synoymous SNP

Answer 16

• 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

Question 17

Describe a nonsynonymous SNP

Answer 17

• Base pair change leads to an amino acid substitution

- May result in change in protein structure, stability, substrate affinity, introduction of a stop codon

Question 18

Describe the relevance of a noncoding SNP

Answer 18

• 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

Question 19

What CNA noncoding SNPs change?

Answer 19

• Transcription factor binding
• Splicing
• Transcript stability
• Enhancer function

Question 20

What are insertions and deletions?

Answer 20

Addition or loss of genetic material

Question 21

What can insertions and deletions lead to?

Answer 21

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

Question 22

What are copy number variations?

Answer 22

CNVs

• CNVs refer to either complete deletion or duplication of a particular gene
• Gain of function or loss of function

Question 23

Describe the diversity of polymorphisms in the population

Answer 23

Different ethnic groups will have different polymorphisms

Question 24

What are cosmopolitan polymorphisms?

Answer 24

Cosmopolitan polymorphisms: polymorphisms common across all ethnic groups

Question 25

What are population polymorphisms?

Answer 25

Population polymorphisms: polymorphisms that differ between groups (ethnic or race)

Question 26

What is the phenotype-to-genotype approach to pharmacogenetics?

Answer 26

Start out by directly measuring pharmacogenetic trait (e.g., the effect of warfarin on blood coagulation)

Question 27

What is a pharmacogenetic trait used for the phenotype-to-genotype approach? What are some examples?

Answer 27

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

Question 28

What are the benefits and disadvantages of using the phenotype-to-genotype approach?

Answer 28

Beneficial because sum of all genes giving rise to an effect

Disadvantages: non-genetic influences giving rise to and unstable responses

Question 29

Describe the process of using the phenotype-to-genotype approach

Answer 29

• 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

Question 30

Describe the cantidate gene approach of the phenotype-to-genotype method?

Answer 30

• 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

Question 31

Describe the genome-wide approach of the phenotype-to-genotype method?

Answer 31

• 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