Lecture 13 + 14 (Cut off for Exam 1)

Question 1

Pharmacogenomics

Answer 1

Science of how genetic variants affect drug action.

Contributes to PK parameters

Question 2

Clinical Consequences (4)

Answer 2

1. Therapeutic failure (not active)
2. Increase adverse side effects
3. Increased toxicity
4. Fatal adverse reactions

Question 3

GINA

Answer 3

• designed to prohibit improper use of genetic info by insurance employment
• Prohibits denial or coverage or higher rates based on genetic predispositions
• Bars employers from firing, hiring, promoting, etc. based on genetic information

Question 4

Human Genome Basics

Answer 4

• 3 billion base pairs (haploid), 6 billion (diploid)
• Approximately 23,000 genes
• Extensive interindividual variation genomic structure
• 99.9% genetically identical between two people, difference in ~1 per 1,000 base pairs
• Bases = integral part of DNA

Question 5

Genes

Answer 5

Sequence of DNA that codes cellular functional units (proteins), multiple gene on each DNA segment. Genes are the exception to the rule though, the majority of DNA isn’t genes.

Question 6

Things to Know

Answer 6

• Basic components of gene structure (introns, exons, coding regions, etc.)
• Know how this connects to the central dogma of biology

Question 7

Types of Genetic Variations

Answer 7

1. Single Nucleotide Polymorphisms (SNPs)
2. Insertions (Indels)
3. Deletions (Indels)
4. Copy Number Variations
   * *NOT MUTATIONS**

Question 8

Alleles

Answer 8

• Genetic variant form of a gene
• Different alleles may be responsible for different in observable phenotypic traits, but also different in response to drug
• MAF - Minor Allele Frequency, an allele occurs in population in reference to most common allele
• Often alleles that are investigated are SNPs

Question 9

SNPs

Answer 9

• Genetic variation that arises when single nucleotide in DNA is different
• Can happen ANYWHERE in DNA (not just coding regions)

Question 10

Possible SNP Consequences

Answer 10

Coding Region:

• Decrease in protein (enzyme) activity compared to common variant
• Increase in enzyme activity
• No change (synonymous SNP)
• *Functional assay needed to identify the effect**

Non-coding Region:

• Decrease in gene expression and therefore decrease in enzyme activity
• Increase in gene expression and therefore increase in enzyme activity
• Increase in the number of copies of an enzyme that leads to increased activity (and vice versa)

Question 11

Association Studies (2)

Answer 11

1. Candidate Gene Approach

2. GWAS

Question 12

Candidate Gene Approach

Answer 12

• Hypothesis Driven
• Pharmacist can participate
• Identify drug response to observable trait

Question 13

3 Candidate Gene Categories

Answer 13

1. Direct Drug Response
2. Signal Transduction Proteins
3. Downstream Proteins

Question 14

GWAS

Answer 14

• Alternate approach to Candidate Gene
• Designed to identify genetic association to an observable response by examining genetic variations across an entire genome
• Doesn’t rely on pharmacology knowledge and isn’t hypothesis driven
• Very successful results
• Includes group with the observable trait and a control group (group without the observable trait)

Question 15

3 Major Divisions of Pharmacogenomics

Answer 15

1. PK - action of body on drug (ADME)
2. PD - action of drug on body
3. Non-PK/PD - adverse reactions

Question 16

PIEU

Answer 16

Variations of Metabolism
P - Poor Metabolizers
I - Intermediate Metabolizers
E - Extensive Metabolizers
U - Ultrarapid Metabolizers

Question 17

P

Answer 17

• Two variant alleles

- No enzyme activity

Question 18

I

Answer 18

• One reduced activity allele

- One null allele

Question 19

E

Answer 19

• At least one normal allele

- “Average”

Question 20

U

Answer 20

• Multiple functional alleles

- Excess enzymatic activity

Question 21

Warfarin

Answer 21

• Can be excreted by CYP2C9
• Acts on Vitamin K epoxide reductase
• Stops activation of clotting factors

Question 22

CYP2C9*2 and *3

Answer 22

• Two non-synonymous SNPs (PK)

- Decrease activity of CYP2C9 to 60-70% (2) or 5% (3)

Question 23

Drug Target Pharmacogenomics

Answer 23

-Newer area
-Any protein involved in drug action is a target
-Seeks to identify how variability in targets affects drugs
-Polymorphisms clearly contribute to the drug response
-Use candidate gene and genomic screens to identify
EX: VKORC1 (PD) in Warfarin activity

Question 24

Haplotypes

Answer 24

Cluster of tightly linked genes on a chromosome that are likely to be inherited together.

Question 25

Mercaptopurine + TPMT

Answer 25

• 6MP is used to treat pediatric leukemias
• TPMT deficiency is inherited
• Polymorphs in TPMT result in decreased activity
• TPMT inactivates 6MP so that its toxic metabolites are cleared
• 6MP’s toxic metabolites can cause myelosuppresion and hepatotoxicity
• This deficiency means you can use smaller doses of the medication to get the same efficacy

Question 26

Irinotecan + UGT1A1

Answer 26

• Campotothein class of topoisomerase inhibitors
• Fight against malignancies like rectal and lung cancers
• Metabolized by carboxylesterases and then UGT1A1 to be excreted

Question 27

UGT1A1*28

Answer 27

• Polymorphisms in UGT1A1 lead to decreased levels of the enzyme
• Causes the toxic, active metabolite SN-28 to not clear which can cause Gilbert’s Syndrome

Question 28

Non-PD/PK Examples

Answer 28

1. HLA-B*5701 + Abacavir

2. HLA-B1502 + HLA-A3101

Question 29

HLA-B*5701 + Abacavir

Answer 29

• Presence of allele could cause Abacavir-induced hypersensitivity reaction, could lead to death
• Fever, rash, GI & respiratory symptoms and malaise

Question 30

HLA-B1502 + HLA-A3101

Answer 30

• Carbamazepines & Phenytoins could lead to cutaneous adverse reaction
• Also Stevens-Johnson Syndrome