Exam V - Genomics Flashcards
1
Q
______________ refers to the variation of a single gene or relatively few genes influencing a drug response
A
Pharmacogenetics
2
Q
___________ encompasses the genome (all genes)
*More than 1 genetic variant
A
Pharmacogenomics
3
Q
The set of observable properties of an organism that are produced by the interaction of the genotype and the environment
*what you see on the pt d/t different genotypes
A
Phenotype
4
Q
The genes that code for a trait
A
Genotypes
5
Q
_______ specify the trait. _______ specify what form the gene takes.
*BLUE BOX
A
-Genes
-Alleles
6
Q
The _________ makes guidelines for using genetics to select meds
A
CPIC
7
Q
Inherited disorder in which the body cannot process the amino acids phenylalanine and tyrosine
A
Alkaptonuria
8
Q
two or more forms of a gene that occupy a specific position on a specific chromosome
A
Allele
9
Q
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
A
Allele Frequency
10
Q
the DNA-containing structure of cellular organisms that contains all or most of the genes of the organism
A
Chromosome
11
Q
the sequence of DNA that occupies a specific position on the chromosome and determines a particular characteristic in an organism
A
Gene
12
Q
a representation of an organisms’ genetic makeup or the particular set of genes that the organism possesses
A
Genotype
13
Q
having two different alleles for the same trait
A
Heterozygous
14
Q
having an identical allele for a single trait
A
Homozygous
15
Q
the observable physical or biochemical characteristics of the organisms genetic makeup
A
Phenotype
16
Q
-a specific genetic alteration; occurs in more than 1% of the population
-Any genetic variation in the DNA sequence
-Can be used interchangeably with variant
A
Polymorphism
17
Q
the most common type of genetic or allelic variation
A
Single Nucleotide Polymorphism (SNPs)
18
Q
Poor metabolizer phenotype
A
PM
19
Q
Intermediate metabolizer phenotype
A
IM
20
Q
Extensive metabolizer phenotype
A
EM
21
Q
Ultra-rapid metabolizer phenotype
A
UM
22
Q
Variations in the DNA sequence that occur in at least 1% of the population
*BLUE BOX
A
Polymorphisms
23
Q
1 nucleotide is exchanged for another in a given position
A
Single Nucleotide Polymorphism (SNPs)
24
Q
Name the 3 areas of variations
A
-Drug-metabolizing enzymes
-Enzyme receptor genes
-Drug transporter genes
25
CYP450 Enzymes are phase ___ enzymes
Phase I
26
(t/f) Genes can be deleted or duplicated
True
27
Duplications __________ the overall activity score
*Increase or decrease
increase
28
What is the range for the allele numbers?
*BLUE BOX (the "normal" on the PowerPoint but this is just stating the total range of allele numbers not the normal value for normal metabolism)
0-3
29
Allele activity score of 0 is what polymorphism
PM
30
Allele activity score of 0.5 is what polymorphism
IM
31
Allele activity score of 1 is what polymorphism
Normal (no polymorphism)
32
Allele activity score of 1-2 is what polymorphism
EM
33
Allele activity score of greater or equal than 2 is what polymorphism
UM
34
Which CYP2D6 alleles are non-functional?
*3
*4
*5
*6
35
Which CYP2D6 alleles are fully functional?
*1
*2
36
Which CYP2D6 alleles have reduced function
*10
*17
*41
37
What is the most common non-functional CYP2D6 allele?
*4
38
Ur doing good
Good job
39
CYP2D6*4 is found w/ a frequency of approximately 20% in the _________ population
European
40
Codeine is a prodrug that is metabolized to ________
Morphine
41
What is the term for the metabolism of codeine to morphine
O-demethylation
42
What is the enzyme responsible for the metabolism of codeine to morphine
CYP2D6
43
With codeine administration, PMs and IMs of CYP2D6 are more likely to experience __________ pain relief
insufficient
44
With codeine administration, UMs of CYP2D6 are at an _________ risk for side effects (drowsiness and respiratory depression) due to higher systemic concentrations of morphine
-increased
45
With codeine administration, PMs of CYP2D6 have ___________ risk of gastrointestinal adverse effects (constipation)
decreased
46
With codeine administration, central side effects (sedation and dizziness) are __________ w/ PMs and EMs
The same
47
The ___________ properties associated with codeine are not affected by CYP2D6 activity.
antitussive
48
According to CPIC guidelines, standard starting doses of codeine are recommended with close monitoring in which two polymorphisms?
Especially in which one?
-EMs & IMs
-IMs
49
Regarding codeine, CPIC recommends use of an alternative agent in which two polymorphisms?
-PMs & UMs
*the two extremes
50
Phase ___ enzyme biotransformation = Conjugation
Phase II
51
Polymorphic Phase II enzymes cause what two things?
-Diminish drug elimination
-Increase risk for toxicities
52
The UGT1A1 Enzyme conjugates _________ ______ into lipophilic molecules
glucuronic acid
53
(t/f) Reduced function polymorphisms of UGT1A1 are common
False
*very rare
54
Regarding the UGT1A1 enzyme, *____ allele is common across 3 major ethnic groups
*28
55
Individuals homozygous for UGT1A1*___ have 60%-70% increased levels of circulating unconjugated bilirubin due to a ~ 30% reduction in UGT1A1 activity (AKA Gilbert's Disease)
*BLUE BOX
*28
56
UGT1A1*28 causes a 60-70% increase in unconjugated ___________ d/t a ___% reduction in the UGT1A1 activity
*BLUE BOX
-bilirubin
-30% reduction
57
UGT1A1*6 and UGT1A1*28 decrease the clearance of ____________
Irinotecan
58
Irinotecan is a ______________ inhibitor prodrug used in first line chemotherapy for certain cancers
topoisomerase I
59
Irinotecan is hydrolyzed by hepatic carboxylesterase enzymes to its cytotoxic metabolite, ____-____, which inhibits topoisomerase I and eventually leads to termination of DNA replication and cell death.
*this is what we want in cancer tx
SN-38
60
With irinotecan, the active ____-____ metabolite is responsible for the majority of therapeutic action as well as the dose-limiting bone marrow and gastrointestinal toxicities
SN-38
61
Which two UGT1A1 polymorphisms cause increased risk for severe life-threatening toxicities, eg, neutropenia and diarrhea, due to decreased clearance of the SN-38 metabolite
*6
*28
62
What should you do to the dose of irinotecan in a pt w/ the homozygous polymorphisms *6 or *28
Decrease starting dose by at least one dose level
63
Transporters work with _________-________ __________
drug-metabolizing enzymes
64
(t/f) Genetic differences in transporter genes may increase risk for toxicities.
True
*they work w/ metabolizing enzymes so polymorphisms of transporters can cause toxicities just like w/ enzymes
65
Plasma membrane transporters are located on __________ cells of many tissues
Epithelial
66
Plasma membrane transporters are located on epithelial cells of what 3 tissues?
-Intestinal membranes
-Renal membranes
-Hepatic membranes
67
The OATP1B1 transporter is encoded by the __________ gene
SLCO1B1
*they transport OATs in Salt Lake City (SLC)
68
The OATP1B1 transporter (encoded by the SLCO1B1 gene) is located on the __________ membrane (facing the blood) of hepatocytes
-sinusoidal
69
The OATP1B1 transporter is responsible for the hepatic uptake of mainly weakly _______ drugs and __________ compounds
-acidic
-endogenous
*you put some acidic fruit in ur OATmeal
70
What 3 drugs/drug classes does the OATP1B1 transporter help metabolize?
-statins
-methotrexate
-bilirubin
*you have to eat OATmeal w/ ur statins b/c you have high cholesterol
71
Over 40 nonsynonymous variants (nsSNPs) have been identified in this gene
SLCO1B1 gene
72
rs4149056
is a common ________ function polymorphism of the SLCO1B1 gene (that codes for the OATP1B1 transporter)
Reduced
*R for Reduced
73
What allele of the SLCO1B1 gene contains only rs4149056?
*5
74
What 2 alleles of the SLCO1B1 gene are haplotypes containing rs4149056 and other variants?
*15
*17
75
a group of alleles in an organism that are inherited together from a single parent.
Haplotype
76
rs4149056 variant is associated with what negative clinical effect?
Simvastatin-induced myopathy
77
What 3 things should you do w/ simvastatin administration if you have alleles *5, *15, or *17 of the SLCO1B1 gene?
-lower the dose
OR
-change to pravastatin or rosuvastatin
-routine CK monitoring
78
What 2 statins should you switch to if you have alleles *5, *15, or *17 of the SLCO1B1 gene?
-Pravastatin
OR
-Rosuvastatin
79
What CPIC level?
genetic info SHOULD be used to change prescribing
(high or moderate evidence)
A
80
What CPIC level?
genetic info COULD be used to change prescribing
(weak evidence w/ little conflicting data)
B
81
What CPIC level?
Commonly used in tests
Evidence varies
No action recommeded
C
*C for commonly
82
What CPIC level?
Don't commonly test
Evidence varies
No action recommended
D
*D for don't commonly test
83
________ ________ ________ system or complex is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans. These cell-surface proteins are responsible for the regulation of the IMMUNE SYSTEM in humans
Human leukocyte antigen (HLA)
84
Polymorphisms in HLA genes are associated w/ what 3 pathologies?
-Stevens-Johnson syndrome
-Toxic epidermal necrosis
-Drug-induced liver injury
85
HLA polymorphisms are associated w/ __________ reactions
hypersensitivity reactions
*H for Hypersensitivity
86
carbamazepine-induced skin toxicities have an increased prevalence in _______ ______ populations
East Asian
87
What 4 drugs are effected by HLA polymorphisms
-Allopurinol
-Carbamazepine
-Abacavir
-Flucloxacillin
*this unit got me ready to HoLA FAAC
88
All inherited causes of pseudocholinesterase deficiency are due to point mutations on chromosome ___
3
89
What are the 2 most common variants of chromosome 3
-A variant
-K variant
*AK 47 (7-4 = 3, chromosome 3)
90
Heterozygous chromosome 3 mutations → prolong relaxation __-__ times longer
3-8
91
Homozygous → prolong relaxation up to ___ times longer d/t no psuedocholinesterase activity, & paralysis up to ______ after single induction dose
-60 times
-8hrs
92
The ___-variant of chromosome 3 is fluoride resistant
F-variant
*F for fluoride
93
What enzyme metabolizes opioids and what 3 opioids are listed in the PP chart (slide 23)
CYP2D6 Enzyme
-Codeine
-Tramadol
-Hydrocodone
94
CYP2D6 w/ opioids:
____ polymorphism → higher risk for life-threatening side effects
UM
*ultra fast conversion to active metabolite (think about prodrug opioids)
95
CYP2D6 w/ opioids:
____ polymorphism → mostly free of any adverse effects
PM
*poor metabolism of prodrug to active metabolite
96
The OPRM1 gene codes for what receptor?
Mu Opioid Receptor (MOR)
*the OPioid Receptor M1 gene (OPRM1) codes for the MOR
97
OPRM1 ____ genotype requires 93% higher morphine dose as compared to the OPRM1 ____
-GG
-AA (normal)
98
Polymorphisms of the __-_________ transporter encoded by the ________ enzyme, effect opioid variability on resp depression
P-glycoprotein
ABCB1
*you can’t sing ur ABCs if ur Pulmonary system is out of breath
99
Polymorphisms of P-glycoprotein transporter is associated with ________ methadone doses in methadone therapy heroin addicts
higher
100
You look at the ______ gene for predicting morphine requirements
COMT
101
_______ mutation is the cause of MH
RYR1
102
The specific mutation in the RYR1 gene in MH is a subsitution of _____ for Arg614
Cys
*don't use succs for intubation in pts w/ MH, use CYSatracurium
103
Chromosome 3 mutations cause what?
Psuedocholinesterase deficiencies
104
The underlying effect of 1 of the triggers of malignant hyperthermia (MH) is the rapid lease of ________ from the _________ _________
Results in a hypermetabolic state
-calcium
-sarcoplasmic reticulum
105
-Central core disease (CCD)
-Myotonic muscular dystrophy
-Centronuclear myopathy
-King-Denborough syndrome
are inherited disorders that are associated with what disorder?
MH
106
____% of patients treated with ondansetron will still experience PONV
35%
107
100_-1-2AAG homomutant deletion polymorphism of 5HT3B receptors does what to PONV risk when administering ondansetron?
Increases PONV risk
*ondansetron isn't gonna work
*my pts PONV went 0-100 real quik
108
DRD2 Taq IA polymorphism of D2 receptors cause a ______ incidence of early PONV
higher
109
Heterozygus or homozygus?
mu-opioid receptor A118G and COMTG1947 A mutation consumed less morphine in the postanesthetic recovery room and had less nausea
Heterozygous = less morphine & nausea
Homozygous = more morphine & nausea
*heterozygous is usually less bad than homozygous
110
What 3 coag factor deficiencies have been consistently shown to correlate with increased propensity for bleeding
-von Willebrand
-Hemophilia A & B
111
Fibrinogen b-chains
455 G/A
854 G/A
Bcl1
are associated w/ increased or decreased levels of fibrinogen?
Increased
*increased risk of thrombotic events
112
Prothrombotic point mutation in factor V (factor V Leiden) results in __________ resistance and can increase the risk of ____ up to 50%
-Protein C
-MI
*Factor V protein C (kinda rhymes)
*VCR (V protein C Resistance)
113
Polymorphisms in what 3 genes can cause post-CABG A-fib
IL-6
ACE
ApOE
114
SNP of the _______ gene predicts post-CABG A-fib w/ 58.8% accuracy
IL-6
115
What 3 meds can offer protection against post-CABG A-fib
Beta-blockers
ACE inhibitors
NSAIDs
*BAN a-fib w/ these drugs
