Test 5: Pharmacogenomics Flashcards by Carol Dumond

What is Pharmacogenetics?

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

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What is Pharmacogenomics?

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

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What is DNA?

-Main constituent of chromosomes
-Carrier of genetic information

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What is an Allele?

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

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What is Allele Frequency?

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.

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What is a Chromosome?

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

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What is a Gene?

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

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What is Genotype?

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

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What is Heterozygous?

Having two different alleles for the same trait

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What is Homozygous?

Having an identical allele for a single trait

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What is Phenotype?

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

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What is Polymorphism?

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

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What is a Single Nucleotide Polymorphism (SNP)?

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

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

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

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

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

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

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

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What are the 3 areas of variations with Polymorphisms?

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

What are the allele activity scores?

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

What is the function of Phase 1 Drug Metabolizing Enzymes?

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

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

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

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

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

What is the function of Phase 2 enzymes?

-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

What are the effects of Phase 2 enzyme polymorphism?

-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

What are the effects from genetic differences in transporter genes?

-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

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

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

What are the example polymorphism of enzyme receptor genes?

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

What is the outcome of HLA-B polymorphism?

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

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

Drug induced: Allopurinol, Carbamazepine, Abacavir, Flucloxacillin

Describe genetic variations and NMB agents.

-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)

What can occur with polymorphism to CYP2D6 as an UM?

Higher risk for life threatening side effects

What can occur with polymorphism to CYP2D6 as an PM?

Mostly free of any adverse effects

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

-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)

What is the opioid transporter and the implications of polymorphism?

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

MH is due to mutation of what receptor?

RYR1 gene

What is the physiology of MH?

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

What are known inherited disorders that are associated with MH?

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

What are 3 receptor types involved in PONV?

1. 5HT3 2. D2 3. MOR

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

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

Atrial fibrillation is associated with polymorphism of:

IL-6 (!) ACE ApOE

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

-Beta-blockers -ACE-inhibitors -NSAIDs