Lecture 9- Pharmacogenetics part II

Question 1

cytochrome P450s

Answer 1

• major drug metabolizing enzymes
• many polymorphisms that affect drug efficacy or toxicity are in the CYP450

Question 2

CYP2D6 consequence

Answer 2

Question 3

nortriptyline

Answer 3

• 2nd generation tricyclic anti-depressant (TCA)
• Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren, Nortrilen
• treats major depression
• inhibits reuptake of norepinephrine/noradrenaline and serotonin to a lesser extent
• narrow TI: therapeutic dose is close to toxic dose
• metabolized by CYP2D6

Question 4

Nortriptyline is metabolized by CYP2D6

Answer 4

poor drug metabolizer

• end up with toxic doses of the drug
• many side effects
• mild: drowsiness, dry mouth, nausea, headache
• serious: seizures, cardiac rhythm disturbances

ultra drug metabolizer

• inactivation of a drug rapidly so it is ineffective

Question 5

variation in drug metabolism of nortriptyline

Answer 5

Question 6

dosage of commonly used anti-psychotics is dependent on:

Answer 6

• dosage of commonly used anti-psychotics is dependent on the CYP2D6 genotype

Question 7

tamoxifen

Answer 7

• treatment for both early and advanced ER+ cancer (estrogen-receptor positive)
• pro-drug that is metabolized by CYP2D6 to its active metabolites (4-hydroxytamoxifen and endoxifen)

Question 8

CYP2D6 allele frequencies

Answer 8

Question 9

Plavix / clopidogrel

Answer 9

• treats blood clots
• pro-drug
• metabolized by CYP2C19 into its active form
• some CYP2C19 alleles result in a poor metabolizer of Plavix resulting in inactive drug
• inactive drug results in possible clots that could lead to myocardial infarction

Question 10

Warfarin/ coumadin

Answer 10

• anti-coagulant = “blood thinner”
• highly prescribed
• often dosing requires modification due to narrow TI
• metabolized by CYP2C9

Question 11

CYP2C9

Answer 11

• 3 allelic variants
• metabolizes warfarin

1. CYP2C9*1 (wild type)
2. CYP2C9*2
3. CYP2C9*3

Question 12

VKORC1

Answer 12

• key rate limiting step in blood clotting
• target of warfarin
• has two major polymorphisms resulting in lower expression resulting in less warfarin dosing being required

1. 1639G > A
2. 1173C > T

Question 13

Warfarin related allele frequencies

Answer 13

Question 14

dose adjustment of warfarin

Answer 14

• based on combinations of CYP2C9 and VCORC1 genotype

Question 15

pharmacogenetics

Answer 15

• looks at specific allele differences within a single gene
• knowledge of target genes ahead of time
• direct link between SNP and phenotype
• require fairly small sample sizes to identify

Question 16

pharmacogenomics

Answer 16

• examines the entire genome for allele differences
• no target known
• identified SNP may have direct link to phenotype
• requires large genome wide association studies

Question 17

The human genome

Answer 17

• 3 billion base pairs
• 3 million SNPs

Question 18

Types of mutations

Answer 18

Question 19

SNP profiles and response to drug therapy

Answer 19

*

Question 20

detecting SNPs

Answer 20

1. isolate DNA
2. digest DNA into “bite size” chunks
3. hybridize onto a matrix containing an array of oligonucleotides representing known SNPs
4. detect signal for each SNP spot on the array

Question 21

pharmacogenomics treatment for hepatitis C

Answer 21

• hepatitis C virus (HCV) leading cause of liver cirrhosis
• recomended treatment: interferons + RIBAVIRIN
• many people aren’t cured by this treatment
• GWAS revealed a region on chromosome 19 was found to correlate with response to interferons

Question 22

___ predicts interferon response in HCV patients

Answer 22

• rs12979860 predicts interferon response in hcv patients
• this polymorphism is in the promoter of the IL28B gene
• IL-28B genotype does not explain all variation in sustained virological response (SVR)

Question 23

how does the increased availability of personal genetic information pose challenges

Answer 23

• privacy
• confidentiality
• discrimination
• psychological impact
• who should have access to stored genetic information? who owns and controls it?
• how can families resolve conflicts when some members want to be tested for a genetic disorder and others do not
• should employers be able to require job applicants to take genetic tests as a condition of employment
• how would you feel if you tested positive for a genetic disordeR?

Question 24

will genetic testing improve outcomes?

Answer 24

1. behavioural changes
2. lack of available treatments

• if someone finds they are genetically susceptible to heart disease would that knowledge change their behavior?
• should genetic tests be made available if there is currently no treatment for the disorder
• should parents have the right to have their minor children tested for adult onset diseases?

Question 25

growing importance of understanding genetics

Answer 25

* public policy decision makers * informed consumers * educated healthcare workers * are politicians and citizens adequately prepared to make policy decisions about genome science? * as more genetic tests become available, will doctors be prepared to answer their patients' questions about these tests?

Question 26

canadian genetic non-discrimination act

Answer 26

* 2017 * can not be penalized for refusing genetic testing * collecting, disclosing, or using genetic test results require written permission * infarctions are subject to fines and/or prison time