Pharmacogenomics

Question 1

Definition of Pharmacogenetics?

Answer 1

Study of sequence variation in individual genes and ther role that plays in determining and individual’s metabolism and response to drugs

Question 2

what racial group has the lowest rate of alcohol abuse?

Answer 2

Asians

Question 3

Why do Asians have a lower rate of alcohol abuse?

Answer 3

Becasue they are more likely to have a genetic makeup that produces less acetylaldehyde dehydrogenase, which leads to accumulation of acetaldehyde and the “Asian flush” (and nausea, vomiting, headache, hypotension)

Question 4

What is the specific variant in acetaldehyde deydrogenase gene that Asians are more likely to have which acts like a “genetic Disulfram”

Answer 4

ALDH2*2

Question 5

Which racial group is more likely to develop esophogeal cancer?

Answer 5

Asians

Question 6

how many protein coding genes are there in the human genome?

Answer 6

20-25k

Question 7

what is the estimated identity of nucelotide sequences between any two individuals?

Answer 7

99.5-99.9%

Question 8

what is the source of the greatest variability in human genetic variation?

Answer 8

single nucleotide polymorphisms (SNPs)

these make up about 80% of all genetic variation

Question 9

what is the definition of an SNP?

Answer 9

a variation in a single nucleotide in a gene that occurs in at least 1% of the population

(less and it is a mutation)

Question 10

how many SNPs are estimated to exist in the human genome?

Answer 10

10-30 million

(approximately 10% in humans have more than 2 possible alleles)

Question 11

2/3 SNPs involve the replacement of cytosine for what?

Answer 11

thymine

Question 12

what is a nonsense mutation?

Answer 12

mutation that results in a change from a coding amino acid to a stop codon

Question 13

what might be the significant of a SNP in a non-coding sequence (i.e., promoter region)?

Answer 13

cound get a promoter sequence that increases gene transcription of the downstream gene

Question 14

what happens there are mutations on the ends of introns?

Answer 14

can lead to loss of the exon or inclusion of the intron into the mRNA and therefore, final product

Question 15

what are the two types of SNP-derived traits?

Answer 15

monogenic (classic Mendelian)

polygenic (continuous variation)

*pentamodal in theory, unimodal in practice

Question 16

what are the three classes of SNPs that modify patient drug responses?

Answer 16

1. metabolize drugs into active or inactive metabolites (e.g., CYPs)
2. drug transporters - move drugs between or out of body compartments or cells
3. target proteins - bind therapeutic drugs resulting in a change in cell physiology

1 and 2 affect pharmacokinetics

3 affects pharmacodynamics

Question 17

What affects the amount of phenytoin that reaches the BBB?

Answer 17

MDR1 - multi-drug resistance protein 1

This is polygenic

Question 18

what happens to phenytoin response if there are SNPs in the voltage-gated Na+ channels?

Answer 18

leads to poor binding affinity and poor therapeutic response

Question 19

What CYP mutations will increase phenytoin blood levels?

Answer 19

CYP2C9 or 2C19

decreases metabolism, increasing blood levels

(ataxia, confusion, slurred speech, decresed coordination)

Question 20

What is the mechanism of action of warfarin?

Answer 20

It inhbits VKORC1, which is the enzyme that reduces Vitamin K (making it active)

Question 21

Which CYP variants are associated with increased bleeding on warfarin?

Answer 21

CYP2C9*2

CYP2C9*3

(*1 is wild-type)

Question 22

There is a SNP in CYP2C9 that is not tested by Nanosphere. Which one is it?

Answer 22

*8, which is the most common SNP in the African American population

Question 23

What is 5-FU converted to as the active metabolite?

Answer 23

5-FdUMP

Question 24

What is the mechanism of action of 5-FU?

Answer 24

Once converted to 5-FdUMP it inhibits thymidylate snynthase, which si required for de novo pyrmidine synthesis, slowing DNA replication

Question 25

What is one mutation that leads to 5-FU toxicity?

Answer 25

DPD, the enzyme that converts 5-FU into 5-FdUMP, leading to poor metabolism

the drug accumulates causing toxicity and bone marrow suppression in this population

*there is a genotype test for this that should be done prior to starting 5-FU therapy

Question 26

What is a second mutation that leads to poor treatment response to 5-FU?

Answer 26

Polymorphisms in thymidylate synthase - triple tandem repeats (most common is double tandem repeast) can sometimes lead to reduced responsiveness to 5-FU

*No approved test for this

Question 27

What percent of ADRs are due to drugs metabolized by CYP2D6?

Answer 27

50%

Question 28

what should you do for a CYP2D6 poor metabolizer for opiod?

Answer 28

don’t give codeine - prodrug that won’t get converted

give hydrocodone or oxycodone instead

Question 29

What CYP2D6 alleles do you see causing ADRs in anti-psychotics?

Answer 29

*3,*4,*5 cause poor metabolism and lead to tardive dyskenesia (decrease dose)

ultra-metabolizer - increase dose

Question 30

What is pharmacogenomics?

Answer 30

study of all variants/polymorphisms that influence a patient’s response to a drug

Question 31

GINA protections don’t apply where?

Answer 31

life insurance

disability

long-term care insurance market