Test 5: Pharmacogenomics

Question 1

What is Pharmacogenetics?

Answer 1

The study of variations in human genes that are responsible for different responses to drug therapy.
-Variation of a single gene (!) or relatively few genes influencing a drug’s response
-Seeks to correlate phenotypic biomarkers with responses

Question 2

What is Pharmacogenomics?

Answer 2

Involves identifying drug response markers at the level of disease, drug metabolism, or drug target.
-Encompasses the genome (all genes - whole genetic makeup)
-Involves DNA sequencing and gene mapping to identify genetic basis for variations in drug efficacy, metabolism, and transport
-Study of how chromosomal variations effect drug response

Question 3

What is DNA?

Answer 3

-Main constituent of chromosomes
-Carrier of genetic information

Question 4

What is an Allele?

Answer 4

2 or more forms of a gene that occupy a specific position on a specific chromosome

Question 5

What is Allele Frequency?

Answer 5

The fraction or percentage of times a specific allele is observed in proportion to the total of all possible alleles that could occur at a specific location on a chromosome.

Question 6

What is a Chromosome?

Answer 6

DNA containing structure that contains all or most of the genes of an organism
-largest is number 1

Question 7

What is a Gene?

Answer 7

A sequence of DNA that occupies a specific position on the chromosome & determines a particular characteristic in an organism.
-Length of DNA that codes for a specific protein

Question 8

What is Genotype?

Answer 8

-A representation of an organism’s genetic makeup or the particular set of genes that the organism possesses
-Ex: BB, Bb, or bb

Question 9

What is Heterozygous?

Answer 9

Having two different alleles for the same trait

Question 10

What is Homozygous?

Answer 10

Having an identical allele for a single trait

Question 11

What is Phenotype?

Answer 11

The observable physical or biochemical characteristics of the organism’s genetic makeup
-Ex: Brown or blue eyes

Question 12

What is Polymorphism?

Answer 12

A specific genetic alteration; occurs in more than 1% of the population.
-Any genetic variation in the DNA sequence (occur anywhere on the genome)
-Can be used interchangeably with variant

Variations in DNA sequence that occur in at least 1% of population

Question 13

What is a Single Nucleotide Polymorphism (SNP)?

Answer 13

The most common type of genetic or allelic variation.
-Pair based substitutions that occur in the genome
-1 nucleotide is exchanged for another in a given position; occur anywhere on the genome
-A.k.a. Point Mutation

Question 14

Genes specify the _____. Alleles specify ________. (Blue Box)

Answer 14

Genes specify the trait. Alleles specify what form the gene takes.

Question 15

What does PM, IM, EM, and UM stand for?

Answer 15

Poor, intermediate, extensive, or ultra-rapid metabolizer phenotype

Question 16

Polymorphisms are variations in the _____ sequence that occur in at least _____% of the population (Blue Box!)

Answer 16

Polymorphisms are variations in the DNA sequence that occur in at least 1% of the population.

Question 17

What are the 3 areas of variations with Polymorphisms?

Answer 17

1) Drug-metabolizing enzymes
2) Enzyme receptor genes
3) Drug transporter genes

Question 18

What are the allele activity scores?

Answer 18

-Range 0 > 3
-0 = PM
-0.5 = IM
-1.0 = normal fxn
-1.0-2.0 = EM
-> 2 = UM

Question 19

What is the function of Phase 1 Drug Metabolizing Enzymes?

Answer 19

-CYP450 enzymes, biotransformation of over 75% of prescription drugs
-Clinical Ex: CYP2D6 – responsible for O-demethylation of Codeine to Morphine

Question 20

What would the effect of PM, IM, EM, and UM due to drug-metabolizing enzymes polymorphisms?

Answer 20

-PM: insufficient analgesia
-IM: insufficient analgesia
-EM: desired effect
-UM: increased adverse effects

Question 21

What is the recommended dosing adjustments for PM, IM, EM, and UM due to drug-metabolizing enzymes polymorphisms?

Answer 21

PM: alternative agent
IM: standard dose
EM: standard dose
UM: alternative agent

Question 22

What is the function of Phase 2 enzymes?

Answer 22

-Conjugation (enhance elimination of endo/exogenous substances)
-Clinical Ex: UGT1A1 – responsible for clearance of Irinotecan
-Conjugates glucuronic acid into lipophilic molecules
-UGT1A1 *6 & *28 decreases the clearance

Question 23

What are the effects of Phase 2 enzyme polymorphism?

Answer 23

-Can diminish drug elimination
-Can increase risk for toxicities

Individuals homozygous for UGT1A1*28 have 60-70% increased levels of circulating unconjugated bilirubin due to a 30% reduction in UGT1A1 activity

Question 24

What are the effects from genetic differences in transporter genes?

Answer 24

-Alter drug disposition and response
-May increase risk for toxicities
-Mediate selective uptake and efflux of endogenous compounds
-Important role in determining plasma and tissue concentrations

Question 25

What is the clinical example associated with drug transporter genes polymorphism?

Answer 25

-OATP1B1 transporter. Fxn:
Hepatic uptake of weakly acidic drugs and endogenous compounds (statins, methotrexate, bilirubin)
-Rs4149056 variant associated with Simvastatin-induced myopathy

Question 26

What are the example polymorphism of enzyme receptor genes?

Answer 26

Polymorphism of HLA genes:
-HLA-B, HLA-DQ, HLA-DR

Question 27

What is the outcome of HLA-B polymorphism?

Answer 27

-Associated with Steven-Johnson Syndrome
-Toxic epidermal necrosis
-Drug-induced liver injury

Question 28

What drugs are associated with hypersensitivity reactions with polymorphism of HLA genes?

Answer 28

Drug induced: Allopurinol, Carbamazepine, Abacavir, Flucloxacillin

Question 29

Describe genetic variations and NMB agents.

Answer 29

-Succs and atypical pseudocholinesterase: Due to point mutations on chromosome 3
-Most common variants: A variant (Asp70Gly), K variant (Ala539Thr)
-Most severe variants: silent! (esp if homozygous)
-Outcome of heterozygous polymorphism: prolong relaxation 3-8 times longer (30-80 minutes)
-Outcome of homozygous polymorphism: prolong relaxation up to 60 times longer (paralysis up to 8 hours, little to no pseudocholinesterase activity)

Question 30

What can occur with polymorphism to CYP2D6 as an UM?

Answer 30

Higher risk for life threatening side effects

Question 31

What can occur with polymorphism to CYP2D6 as an PM?

Answer 31

Mostly free of any adverse effects

Question 32

What is the Opioid receptor gene and the implications of polymorphism?

Answer 32

-OPRM1 gene
-Specific polymorphism R gene name: OPRM1 GG genotypes

This polymorphism Implication:
-Requires 93% higher morphine doses as compared to the OPRM1 AA genotype (codes for the MOR)

Question 33

What is the opioid transporter and the implications of polymorphism?

Answer 33

P-glycoprotein
-effect opioid variability on respiratory depression, associated with higher methadone doses in methadone therapy heroin addicts

Question 34

MH is due to mutation of what receptor?

Answer 34

RYR1 gene

Question 35

What is the physiology of MH?

Answer 35

-Substitution of Cys for Arg614
-Increased calcium and hypermetabolic state

Question 36

What are known inherited disorders that are associated with MH?

Answer 36

Central core disease (muscle weakness), Myotonic muscular dystrophy, Centronuclear myopathy, King-Denborough syndrome

Question 37

What are 3 receptor types involved in PONV?

Answer 37

1. 5HT3
2. D2
3. MOR

Question 38

What polymorphisms are associated with thrombotic outcomes after cardiac surgery (CVA, PE, coronary graft thrombosis)?

Answer 38

Associated with elevated fibrinogen levels:
-Fibrinogen b-chain 455 G/A,
-Fibrinogen b-chain 854 G/A
-Fibrinogen b-chain Bcl1,

-Consistently associated with arterial thrombotic disease
-Risk factor for ischemic stroke, MI and PVD
-No recommendation for screening due to the lack of evidence to indicate any prognostic or therapeutic consequence within the general population

Question 39

Atrial fibrillation is associated with polymorphism of:

Answer 39

IL-6 (!)
ACE
ApOE

Question 40

What are suggested treatments post-CABG to prevent A Fib?

Answer 40

-Beta-blockers
-ACE-inhibitors
-NSAIDs