Pharmacogenetics

Question 1

What is one of the leading causes of hospitalization and death in the US?

Answer 1

Adverse drug reactions

Question 2

What term can be used to describe current pharmacologic practice?

Answer 2

“One size fits all” > based on the “average” patient

Question 3

What is the role of G6PD in the body?

Answer 3

Supplies NADPH and glutathione in RBC’s

Question 4

What is the nature of a G6PD deficiency mutation and what are the most common types?

Answer 4

Mutation is sex-linked and carried on X chromosome; SNPs

Question 5

What is the main difference between pharmacogenetics and pharmacogenomics?

Answer 5

Pharmacogenetics focuses on a single gene and pharmacogenomics focuses on a multi gene approach

Question 6

What are most drugs metabolized by?

Answer 6

A Cyp450 subtype

Question 7

What are SNPs?

Answer 7

Small nucleotide changes, most common polymorphism

Question 8

What are chromosomal insertions or deletions and what do they cause?

Answer 8

That are large sequence changes and can cause frameshift mutations

Question 9

What is a frameshift mutation?

Answer 9

Insertion or deletion that alters the reading frame of a gene

Question 10

What is a missense mutation?

Answer 10

Substitution that results in a different amino acid

Question 11

What is a nonsense mutation?

Answer 11

Substitution that results in a stop codon

Question 12

What is a silent mutation?

Answer 12

Substitution that results in no significant effects

Question 13

What is an in-frame deletion or insertion?

Answer 13

Deletion or insertion of 3 nucleotides that introduces or removes an amino acid into the protein, but does not alter the reading frame

Question 14

What is a neutral mutation?

Answer 14

Changes in amino acid sequence of a protein without altering its ability to function

Question 15

What is a loss of function mutation?

Answer 15

Causes a complete or partial loss of a function of the protein

Question 16

What is a gain of function mutation?

Answer 16

Causes over-activity of the protein or the appearance of a new trait or function

Question 17

What causes over 90% of human genetic variation?

Answer 17

SNPs

Question 18

What is personalized medicine?

Answer 18

Identifying all the SNPs in patients before prescribing them drugs.
-Allows researches to study all alleles to see if there will be adverse effects

Question 19

What are the important proteins and genes involved in drug metabolism

Answer 19

G6PD, 2D6, and NAT2

Question 20

Most mutations can be categorized in two areas. What are they?

Answer 20

1) Changes in gene copy number

2) changes in function of protein

Question 21

What does a change in gene copy number result in?

Answer 21

Gene duplications, nonsense mutations, and gene deletion (Loss of function mutations)

Question 22

What enzyme is associated with metabolism of the drugs Debrisoquin, Codeine, and Nortripyline?

Answer 22

Cyp2D6

Question 23

What drugs does NAT2 metabolize?

Answer 23

Hydralazine, Isoniazid, and pracainamide (HIP drugs)

Question 24

How does NAT2 change protein function?

Answer 24

Transfers and acetyl group from acetyl CoA to the acceptor amine, resulting in formation of an amide on the drug

Question 25

Is rapid acetylation dominant or recessive? What does it do to NAT2 activity and what does that result in?

Answer 25

Dominant
Increases NAT2 activity
Results in hepatotoxicity

Question 26

Is slow acetylation dominant or recessive? What does it do to NAT2 activity and what does that result in?

Answer 26

Recessive
Decrease NAT2 activity
Results in Lupus

Question 27

What is the phenotype of slow acetylators?

Answer 27

Homozygous for the slow allele (rr)

Question 28

What is the phenotype for rapid acetylators?

Answer 28

Either homozygous or heterozygous for the rapid allele (RR or Rr)

Question 29

What is the second most common metabolizing enzyme?

Answer 29

CYP2D6

Question 30

What can mutations in CYP2D6 result in?

Answer 30

Deletions, duplications, and SNPs

Question 31

Where is the OATP1B1 receptor located? What does it do?

Answer 31

Sinusoidal membrane of hepatocytes.

Hepatic uptake of weakly acidic drugs and endogenous compounds

Question 32

What does a mutation in OATP1B1 result in?

Answer 32

Reduced response to HMG-coenzyme A reductase inhibitors (statins) which can lead to decreased serum lipids

Question 33

What is the human leukocyte antigen (HLA) involved in?

Answer 33

Immune system/response and hypersensitivity reactions such as SJS

Question 34

The hypersensitivity response from HLA is mediated by what?

Answer 34

Cytotoxic CD8 T cells

Question 35

What does the HLA-B*5701 variant result in?

Answer 35

Abacavir-induced skin toxicity

Question 36

What is genotyping?

Answer 36

Analysis of gene variants that lead to prediction of phenotype

Question 37

What is phenotyping?

Answer 37

Using a probe drug to evaluate ratio of metabolite to drug

Question 38

What enzyme is involved in the metabolism of Dibucaine?

Answer 38

Serum cholinesterase