Pharmacogenomics Exam 3 Flashcards
(194 cards)
1
Q
What is an allele?
A
An allele is one pair of genes. It is commonly used to describe alternative forms of a gene at a given locus (locus is the location of a gene or DNA marker on a chromosome).
2
Q
What is a genotype?
A
The genotype refers to the set of alleles for a particular gene or locus. A genotype describes two alleles on homologous chromosomes. Like A/a, B/b etc.
3
Q
What is a haplotype?
A
This is a combination of set of alleles that are inherited on the same chromosome. It is the set of alleles or SNPs on the chromosome.
4
Q
What is a diplotype?
A
A diplotype describes two haplotypes on homologous chromosomes. It is a pair of haplotypes. Two haplotypes (one from each parent) form a diplotype. For example, an individual might inherit a maternal haplotype of A B C D and a paternal haplotype of a b c d, forming a diplotype of A B C D/a b c d.
5
Q
What does homozygous mean?
A
Homozygous refers to the genotype. It means that there are two identical alleles.
6
Q
What does heterozygous mean?
A
Heterozygous refers to the genotypes. It means that are two different alleles.
7
Q
What are the different types of genetic variations?
A
Polymorphisms, mutations, and single nucleotide polymorphisms (SNPs)
8
Q
What is a polymorphism?
A
This is a type of genetic variation. A polymorphism is an allele present in more than 1% of the population. It contributes to diversity within a population and is not usually associated with severe disease.
9
Q
What is a mutation?
A
This is a type of genetic variation. This is a rare allele found in less than 1% of the population. It is commonly due to environmental factors or DNA copying errors.
10
Q
What is the difference between a polymorphism and a mutation?
A
Polymorphisms occur in more than 1% of the population while mutations occur in less than 1% of the population.
11
Q
What is an SNP?
A
This is a type of genetic variation when one nucleotide or base pair is substituted for another at a particular position within the genome.
12
Q
What are the types of coding region variants?
A
- Synonymous variant
- Nonsynonymous variant
- Missense (part of nonsynonymous)
- Nonsense (part of nonsynonymous)
13
Q
What is a synonymous variant?
A
This is a coding region (exon) variant. It is a silent polymorphism. It is when a single nucleotide changes in the coding region of the DNA sequence and it does not lead to changes in the AA sequence.
14
Q
What is a nonsynonymous variant?
A
This is a coding region (exon) variant. It is a nonsynonymous polymorphism. This is when a single nucleotide change in the coding region now specifies a different AA that may lead to a potential change to protein activity or function.
15
Q
What is a missense variant?
A
This is a type of nonsynonymous variant where there is a single nucleotide change leading to a different AA in the protein.
16
Q
What is a nonsense variant?
A
This is a type of nonsynonymous variant where there is a single nucleotide change resulting in a stop codon.
17
Q
What are the functional outcomes for nonsense coding region variants?
A
Nonsense variants in coding regions introduce premature stop codons, leading to truncated, nonfunctional proteins or mRNA degradation via nonsense-mediated decay, often resulting in loss of gene function.
18
Q
What are the functional outcomes for an insertion frameshift mutations?
A
Insertion frameshift mutations disrupt the reading frame, leading to altered amino acid sequences and often premature stop codons, resulting in dysfunctional or nonfunctional proteins.
nsertion frameshift mutations occur when one or more nucleotides are added to the DNA sequence, disrupting the reading frame of the gene. This shift alters how the codons are read during translation, often leading to a completely different and usually nonfunctional protein, with possible premature stop codons.
19
Q
What are the functional outcomes for a deletion frameshift mutations?
A
A deletion frameshift mutation occurs when one or more nucleotides are removed from the DNA sequence, disrupting the reading frame of the gene. This causes a shift in how codons are read during translation, leading to altered amino acid sequences and often a nonfunctional protein with possible premature stop codons.
20
Q
What do variants in the coding region do to genes?
A
Variants in the coding region can alter the protein sequence, potentially affecting its function. They may lead to changes like missense mutations, truncations, or altered expression levels.
21
Q
What do variants in the noncoding region do to genes?
A
Variants present in the noncoding regions may alter transcription factor binding to either increase or decrease transcription.
22
Q
What do variants in the promoter region do to genes?
A
Changes in promoter and enhancer sequences can impact transcription factor binding and subsequent gene transcription.
23
Q
What are the major types of chromosomal variants?
A
Inversion and translocation
24
Q
What is inversion?
A
This is a chromosomal mutation where a small or large amount of bases in DNA are reversed. It can result in loss of function.
25
What is translocation?
This is a chromosomal mutation where a segment of one chromosome is transferred to another non-homologous chromosome (not the same chromosome).
26
What is pharmacogenetics?
How a variation in one single gene influences a response to a drug.
27
What is pharmacogenomics?
How all of the genes (the genome) can influence response to a drug. This is more of a global term.
28
What part of PK can genetic variants influence?
Pharmacokinetics genetic variants influence all of ADME! Genetic variants in metabolizing drug enzymes can impact the rate of drug metabolism. Genetic variants in transporters could impact the rate of drug absorption, distribution, and excretion
29
What part of PD can genetic variants influence?
Pharmacodynamic variants can modify drug targets.
30
What is the number of clinically actionable germline genes?
Only 30 genes are considered to be clinically actionable germline genes.
31
What is a germline genetic variation?
Germline genetic variations are inherited genetic variants that are present in every cell in the body that have a nucleus.
32
What is a somatic genetic variation?
Somatic genetic variations are not inherited but acquired. They are not present in every cell.
33
What is the difference germline and somatic genetic variation?
Germline variants are inherited and present in every cell while somatic variants are not inherited but acquired and not present in every cell.
34
What are X-linked dominant inheritance patterns?
Females have 2 X chromosomes so a mutation in one copy is enough to cause that disorder. Males have 1 Y and 1 X so a mutation in only one copy of the gene causes the disorder.
35
What are X-linked recessive inheritance patterns?
In females, the mutation would need to be present on both copies to have the disease but for males only one copy needs to be present for the disease. This is why males have a higher prevalence of X-linked variants.
36
Male are XY and females are XX. How are Y-linked inheritance patterns passed down?
Only males have the Y chromosome so mutations can only be passed from father to son.
37
What is the main goal of the CPIC?
CPIC's goal is to address the barrier to clinical implementation of pharmacogenetic test by creating, curating, and posting freely available, peer-reviewed, evidence-based, updatable, and detailed gene/drug clinical practice guidelines. It gives evidence on how to apply pharmacogenetic results into patient care.
38
What are the basic levels of evidence for PharmGKB?
Level 1A- high evidence of variant-drug combination
Level 1B- high evidence of variant-drug combination
Level 2A- moderate evidence
Level 2B- moderate evidence
Level 3- Low evidence
Level 4- preliminary evidence
39
What is the drug Rasburicase?
Rasburicase is a recombinant urate oxidase enzyme that breaks down excess uric acid seen in tumor lysis syndrome present in hematological cancers where rapidly dividing cells lyse rapidly and release uric acid.
40
Why is glucose-6-phosphate dehydrogenase important when taking the drug rasburicase?
Rasburicase breaks down the uric acid from dying cancer cells into H202 and CO2. These products will enter the pentose phosphate pathway and glucose-6-phosphate dehydrogenase (G6PD) will break them down into NADPH and protect cells from oxidative stress.
41
How do variants in glucose-6-phosphate dehydrogenase result in rasburicase drug toxicity?
Variants in G6PD make the enzyme decrease or loss its function. Loss of this enzyme due to variations leads to increased susceptibility to stressors.
42
What types of samples are collected for genomic DNA testing?
1. Blood (DNA from lymphocytes)
2. Saliva/ cheek brushing
3. Whole saliva
43
What are the main steps of PCR?
The goal of PCR is to made a bunch of DNA!
1. Denaturing
2. Annealing
3. Extension
DAE
44
Explain the denaturing steps of PCR.
This is when the mixture of DNA with other components like primers, nucleotides, Taq polymerase, and mix buffer, are heated and it makes the double stranded DNA come apart into single strands.
45
Explain the annealing steps of PCR.
This is when the DNA mixture for the PCR is cooled down so the primeres can anneal a complementary DNA sequence for the single strand of DNA.
46
Explain the extension steps of PCR.
This is when the DNA mixture is warmed up to activate the DNA polymerase Taq enzyme. It will find the primer bound to single strand DNA and begin adding base pairs to create newly formed double stranded DNA.
47
What is Sanger Sequencing?
This is a method to detect differences in individual alleles. It uses dideoxynucleotide chain terminators in the PCR to create specific size PCR products. It has to be user defined gene target. The results will produce those exact DNA sequence.
48
What is the TAQMAN AS reaction?
This is a method to detect differences in individual alleles. This uses a combination of DNA primer and allele specific fluorescent probes to detect the specific alleles. It is fairly easy, cost effective, medium throughput, and allows you to tell the presence or absence of specific base pair variants.
49
What is a genechip/microassay?
This is a method to detect differences in individual alleles. This is also called hybridization. It uses allele specific oligonucleotides hybridization and allows looking at thousands of polymorphisms at one time. It promotes discovery this way.
50
What is Next-generation sequencing?
This is a method to detect differences in individual alleles. This is also known as high-throughput screening or massive parallel sequencing. It allows for sequencing of DNA and RNA very quickly and cheaply.
51
What are the 4 main steps of next-generation sequencing?
1. Library preparation
2. Cluster amplification
3. Sequencing
4. Alignment and data analysis
52
What is GWAs?
This is a genome wide association study that seeks statistical associations between genetic loci and a phenotype of interest. Basically, a phenotype is selected and the DNA data set is made from all different people and SNPs associated with those phenotypes can be identified.
53
What is the basic requirement needed to perform a GWA study?
GWAs need to use well defined cohorts of subjects with and without the qualitative trait.
54
How is an activity score from a functional variant calculated?
The activity score of a variant is calculated by adding up the values associated with each allele present.
55
How is the activity score for functional variants ranked?
>1= increased function
1 or >1= normal or increased function
1= normal function
0.5= decreased function
0= no function
56
What is the definition of the metabolic phenotype UM?
UM is an ultra-rapid metabolizer that can occur due to an increased number of copy variants and/or polymorphisms increasing function.
57
What is the definition of the metabolic phenotype EM/NM?
EM/NM used to be called normal metabolizer but is now called extensive metabolizer. This is considered normal or wild-type with 1* alleles.
58
What is the definition of the metabolic phenotype IM?
IM is an intermediate metabolizer where enzyme function is decreased but still present. One allele could be decreased or non-functional and the other allele is normal.
59
What is the definition of the metabolic phenotype PM?
PM means poor metabolizer meaning that enzyme function is severely decreased or non-functional. This typically occurs when there are no functional alleles present.
60
What is the interaction between CYP2C9 and Celecoxib?
Around 75% of the metabolism of Celecoxib is done by CYP2C9.
61
How do the CYP2C9*2 and 3 variants impact Celecoxib metabolism, efficacy, and toxicity?
CYP2C9*2 and *3 result in decreased function of the enzyme that metabolizes Celecoxib. This results in higher blood concentrations of the drug resulting in a higher chance for toxicities like GI bleeds.
62
What is unique about CYP2D6?
CYP2D6 is the main non-inducible CYP450 enzyme meaning certain drug can not upregulate or downregulate it. Most changes in the activity of this enzyme is due to genetic variations.
63
What is the drug Isoniazid?
This is an antibiotic used to treat tuberculosis. It is an inactive prodrug that is activated inside of bacteria.
64
What are the interactions between NAT2 and Isoniazid?
Isoniazid is metabolized in via two pathways; NAT2 and hydrolysis. The products formed in the hydrolysis pathway are toxic metabolites to the liver.
65
How do slow NAT2 variants impact Isoniazid metabolism, efficacy, and toxicity?
Slow acetylators will have higher concentrations of Isoniazid and metabolism of the drug will more likely follow the hydrolysis pathway leading to the production of more toxic metabolites. It is better to give slow acetylators less of this drug.
66
How do fast NAT2 variants impact Isoniazid metabolism, efficacy, and toxicity?
Fast acetylators are more prone to fail treatment as the body is rapidly inactivating the drug to be excreted. In order to TX to be effective, more of this drug should be given to the person.
67
What is unique about the phase 2 metabolism enzyme UGT1A1?
It is the sole enzyme responsible for the breakdown of bilirubin.
68
How does atazanavir interact with UGT1A1?
Atanzanir, an HIV protease inhibitor, actually inhibits UGT1A1 which will increase plasma bilirubin levels.
69
How do extensive metabolizers for UGT1A1 impact those prescribed Atazanavir?
It does not impact them much as the Atazanavir will not shut off all function.
70
How do poor metabolizers for UGT1A1 impact those prescribed Atazanavir?
Additional suppression of UGT1A1 by Atazanavir can drive bilirubin concentrations high enough to cause bilirubin related disorders like jaundice.
71
What are ABC transporters?
One of the major superfamilies of transporters. This is an ATP dependent EFFLUX transporter. They can go against concentration gradients.
72
What are SLC transporters?
One of the major superfamilies of transporters. It can be both active and passive transport and is the major INFLUX transporter (some can act as efflux though).
73
What are the 3 types of SLC transporters?
1. Membrane channels- large proteins that function as pores
2. Facilitative transporters- facilitated diffusion that follows the concentration gradient
3. Secondary active transporters- similar to facilitated diffusion but has two substances binding. It can be symport or antiport.
74
What are the characteristics of SLCO1B1 (OATP1B1)?
It is an organic anion transporter that functions in influx that is mainly expressed in hepatocytes. It transporters compounds from the blood into the liver.
75
How do common variants in SLCO1B1 impact its functional effect?
Variations that change the function of this transporter will reduce the transport function.
76
What is unique about the *5 allele for SLCO1B1?
With the *5 allele, there is a decrease in the number of transporters on the cell surface which inhibits their ability to transport substances into hepatocytes.
77
What is the MOA of statin drugs?
Statins are used to treat primary hypercholesterolemia. It inhibits the production of endogenous cholesterol production by inhibiting HMG-CoA reductase.
78
What is the relationship between statins and SLCO1B1?
Statins are taken up in the intestines and transported from the blood into the liver by SLCO1B1. Once in the liver, statins are targeted for degradation by CYP450 enzymes.
79
How do SLCO1B1 variants impact statin transport, metabolism, and toxicity?
SLCO1B1 variants that are low functioning will result in less statin uptake into the liver. This means that there will be more circulating drug in the blood which can increase the risk for toxicity like SAMS (Statin-associated muscle symptoms).
80
T or F: Rosuvastatin is extensively metabolized and excretion of the active drug is not dependent on efflux pumps.
False. Rosuvastatin is not extensively metabolized and its excretion of the active drug is highly dependent on efflux pumps.
81
Why do variants in ABCG2 impact rosuvastatin?
ABCG2 is a main player in the excretion of active rosuvastatin.
82
How do variants in ABCG2 impact rosuvastatin metabolism, efficacy, and toxicity?
Poor ABCG2 function is associated with higher levels of rosuvastatin in the blood which can lead to toxicities.
83
Which CYP450 enzyme is the primary metabolizer of fluvastatin?
CYP2C9
84
Why do variants in CYP2C9 impact fluvastatin?
CYP2C9 is the main enzyme that metabolizes fluvastatin. Variants in this enzyme will impact the metabolism of this drug.
85
How do variants in CYP2C9 impact fluvastatin metabolism, efficacy, and toxicity?
Those with poor metabolizer variants will have increased concentrations of fluvastatin in the body which can increase the risk for toxicity.
86
Explain the connection between HIV and CCR5 and CXCR4?
HIV binds utilizes two coreceptors, the CXCR4 and CCR5 (chemokine receptor #5) to enter T cells. The M-tropic strain of HIV enters the cell using CCR5 while the T-tropic HIV strain uses the CXCR4 to enter to T cell.
87
T or F: Individuals homozygous for CCR5 d32 allele are almost completely resistant to HIV infection from CCR5 dependent M-tropic strains.
True
88
What are the key interactions between CCR5 and Maraviroc?
Maraviroc is a CCR5 antagonist. It lowers the burden of HIV viral copies and increases CD4 immune cells (T helper cells). This drug only works for the CCR5 dependent strain with is the M-strain
89
How did CCR5 variants play a key role in the development of the drug Maraviroc?
Those with nonfunctional alleles for CCR5 were resistant to M-Tropic strains of HIV. Developers of the drug Maraviroc believed they could antagonize the CCR5 receptor to stop HIV from binding and entering T cells.
90
Maraviroc disrupts the binding of HIV virus to the _________ co-receptor, preventing viral entry into immune cells.
a. CXCR4
b. CCR5
c. CD3
d. ADBR1
B. CCR5
91
What are the defects present in CFTR variants?
The CFTR allele causing cystic fibrosis is an autosomal recessive variant. There are different types of alleles that cause cystic fibrosis like F508del (type II CF) and G551D (type III CF).
92
How is CFTR affected by the F508del allele that results in type II cystic fibrosis?
There is a defect in the protein tracking to the cell surface. This is the most common variation.
93
How is CFTR affected by the G551D allele that results in type III cystic fibrosis?
This is when the protein gets made and gets to the cell surface but it has gating issues and does not work well.
94
What is CFTR?
CFTR is the cystic fibrosis transmembrane conductance regulator that is an ABC transporter unique to transporting chloride. It plays an essential role in regulating water and salt movement across epithelial tissues.
95
What CFTR variant classes are targeted by Ivacaftor?
Ivacaftor targets class III variants (G551D) for cystic fibrosis. It is a CFTR potentiator drug that increases the CFTR channel gating to enhance chloride transport.
96
What CFTR variant classes are targeted by lumacaftor/tezacaftor?
Lumacaftor/tezacaftor targets class II variants (F508) for cystic fibrosis. It is a CFTR corrector drug. It works the best in those who are homozygous for the F508 allele.
97
What is the drug Trikafta?
This drug include all three cystic fibrosis drugs that target class II and III, tezacaftor and ivacaftor, as well as a new drug called Elexacaftor.
98
What CFTR variant classes are targeted by elexacaftor?
Elexacaftor is a dual function CFTR modulator with both potentiator and corrector activity. It can be used for patients with single class II F508del CFTR allele.
99
What is the MOA of the drug Abacavir?
Abacavir is a nucleoside reverse transcriptase inhibitors prodrug used in to treatment of HIV. It blocks the conversion of HIV RNA to HIV DNA.
100
How does HLA (Human leukocyte antigens) work?
HLA class I molecules are expressed on all cells and are responsible for presenting normal self peptides to immune cells. If infected, they also present pathogen peptides which is sensed as non-self by immune cells.
101
What is the mechanism behind HLA-B5701 variant causing hypersensitivity reactions following treatment with Abacavir?
Normally Abacavir does not bind to HLA-B receptors. However, the HLA-B*5701 variant alters the structure of the receptor and promotes the binding of Abacavir to it. When Abacavir binds to it, the cell produces an active T-cell response which release inflammatory cytokines which can induce a hypersensitivity reaction.
102
How does HLA-B and Abacavir interaction?
In those with normal HLA, Abacavir should not bind the HLA-B receptor.
103
Ivacaftor is effective by itself in cystic fibrosis patients with which class of CFTR genetic variants?
A) Class 1
B) Class 2
C) Class 3
D) Class 4
C. Class 3
104
IV-positive individuals who carry the HLA-B*5701 genetic variant show a significantly
increased risk of abacavir hypersensitivity. This is due to:
a. Abnormal binding of abacavir to HLA-B*5701
b. Increased metabolic inactivation of abacavir by HLA-B*5701
c. Decreased metabolic inactivation of abacavir by HLA-B*5701
d. Increased efflux transport of abacavir by HLA-B*5701
A. Abnormal binding of abacavir to HLA-B*5701
105
What is MN-RNR1?
MN-RNR1 is a mitochondrial gene that encodes the 12S rRNA subunit which is needed for the translation of mRNAs into proteins.
106
What are aminoglycosides?
Aminoglycosides are antibiotics that bind to the 30S ribosomal subunit of bacteria to inhibit initiation.
107
Why do genetic variants in MN-RNR1 result in enhanced aminoglycoside related toxicity which causes hearing loss?
There are mitochondrial ribosomes on hair cells in the ear. MN-RNR1 encodes for 12S rRNA in human mitochondria and it looks similar to prokaryotic 16S rRNA subunit. With variants in the MN-RNR1, it makes the 12S subunit look even more similar to the bacterial 16S subunit. This makes the aminoglycosides bind to it and the hair cells die causing hearing loss.
108
What is the MOA of the drug clopidogrel?
It is an irreversible inhibitor of P2Y12 receptor prodrug and blocks the aggregation of platelets for their lifetime (10days).
109
What is the normal interaction between CYP2C19 and clopidogrel?
Normally, clopidogrel is metabolised by CYP2C19 into its active form.
110
How do variants in CYP2C19 impact clopidogrel metabolism, efficacy, and toxicity?
It was shown that those with poor and intermediate metabolizer allele had higher levels of inactive clopidogrel in their blood which decreased the efficacy of the the drug. Better efficacy of the drug is not seen in those who are extensive or ultra metabolizers though.
111
Why are alternative therapies to clopidogrel not impacted by CYP2C19 variants?
The alternative therapies are not prodrugs and do not need to be activated by an enzyme so their ability to be efficacious is not affected by enzymatic activity.
112
What is the effect of CYP2C19 poor metabolizer phenotypes on Clopidogrel activity?
a. Reduced platelet aggregation
b. Increased drug metabolism
c. Reduced active metabolite formation and decreased antiplatelet effect
d. No effect on drug metabolism
C. Reduced active metabolite formation and decreased antiplatelet effect
113
What is the MOA of warfarin?
Warfarin blocks blood clotting by blocking the vitamin K epoxide reductase enzyme (VKORC1). It is has two enantiomers, R and S. The S form has a larger inhibitory effect on VKORC1 and is metabolized into its inactive form by CYP2C9.
114
How do CYP2C9 variants impact warfarin metabolism, efficacy, and toxicity?
CYP2C9 variants can lower metabolic activity of the enzyme and can result in increased concentrations of the S-warfarin meaning that more active drug will be in the system longer.
115
How do VKORC1 variants impact warfarin pharmacodynamics, efficacy, and toxicity?
The vitamin K Epoxide Reductase enzyme also has polymorphisms that can lower the expression level of the enzyme. Haplotype A (homozygotes A/A) show lower VKORC1 expression and therefore need a lower dose of warfarin. Haplotype G (homozygotes G/G) show higher VKORC1 expression and therefore need higher doses of warfarin.
116
T or F: Those with the VKORC1 haplotype A need a larger dose of warfarin as they have higher VKORC1 expression.
False. Haplotype A shows lower expression of VKORC1 so less warfarin dose is needed.
117
How do variants in CYP2C9 and VKORC1 impacts warfarin?
Integration of CYP2C9 and VKORC1 variants to determine optimal warfarin dosing for patients.
118
Warfarin dosing is influence by genetic variations in:
a. VKORC1 and CYP2C9
b. SLCO1B1 and CYP2C9
c. VKORC1 and CYP2D6
d. CYP2C19 and VKORC1
A. VKORC1 and CYP2C9
119
Genetic variants that alter VKORC1 expression impact warfarin dosing and efficacy. VKORC1 genetic variations impact warfarin.
a. Pharmacokinetics
b. Metabolism
c. Pharmacodynamics
d. Transport
C. Pharmacodynamics
120
Which patient population would likely require the lowest dose of warfarin based on the genetic variants below?
a. High expression of VKORC1 and CYP2C9 extensive metabolizer
b. Low expression of VKORC1 and CYP2C9 poor metabolizer
c. High expression of VKORC1 and CYP2C9 poor metabolizer
d. Low expression of VKORC1 and CYP2C9 extensive metabolizer
B. Low expression of VKORC1 and CYP2C9 poor metabolizer
121
Explain the relationship between codeine and CYP2D6.
Codeine is a kind of prodrug that has a weak affinity for the mu-opioid receptor. 5-15% of codeine is metabolized by CYP2D6 into morphine while the rest is made inactive by other enzymes.
122
How do CYP2D6 variants impact codeine metabolism, active metabolite levels (morphine), efficacy and/or toxicity?
Those who are poor metabolizers for CYP2D6 have more codeine converted to its active form through other pathways leading to insufficient pain relief. Those who are ultra rapid metabolizers have more codeine get converted to the active form of morphine and are at higher risk for toxicity.
123
Which metabolic phenotype would you expect to find the highest morphine plasma levels following codeine administration?
a. CYP2D6 EM
b. CYP2D6 UM
c. CYP2D6 IM
d. CYP2D6 PM
B. CYP2D6 UM
124
Which metabolic phenotype of CYP2D6 is associated with a lack of efficacy when using codeine?
A) Ultra-rapid metabolizer (UM)
B) Extensive metabolizer (EM)
C) Poor metabolizer (PM)
D) Intermediate metabolizer (IM)
C. Poor metabolizer (PM)
125
What is the MOA of PPIs?
Proton Pump Inhibitors like Omeprazole block the acid secretion from parietal cells in the stomach and provide relief from acid-related disorders. These drugs are activated by low pH levels (very acidic) and covalently bind to parietal cells until they die and new ones are made.
126
What is the relationship between PPIs and CYP2C19?
PPIs are active in the stomach but are mainly metabolized by CYP2C19 and CYP3A4. CYP2C19 is the main enzyme that converts omeprazole into its inactive form.
127
How CYP2C19 variants impact omeprazole metabolism, drug levels, efficacy and/or potential adverse reactions?
CYP2C19 poor and intermediate metabolizers have a huge increase and better response to omeprazole while ultra rapid and extensive metabolizers have decreased levels and reduced responses to omeprazole. For EM and UM it is recommended to give higher doses.
128
Which genotype would you expect to find the highest omeprazole (OME) plasma levels after giving a standard dose?
a. CYP2C19 UM
b. CYP2C19 EM
c. CYP2C19 IM
d. CYP2C19 PM
D. CYP2C19 PM
129
T or F: An individual is CYP2C19 PM. Relative to a CYP2C19 EM, treatment with Omeprazole results in a shorter % of time with an acidic gastric pH level
True
130
The alternative antiplatelet therapy ticagrelor is recommended for CYP2C19 intermediate and poor metabolizers because:
a. it is metabolized by CYP2C19
b. its activity is not dependent on CYP2C19 metabolism
c. its activity is dependent on CYP2C19 metabolism
d. it blocks the P2Y12 receptor by reversible binding
B. Its activity is not dependent on CYP2C19 metabolism
131
What enzymes play a major role in the metabolism of numerous neuropsychiatric medications?
CYP2D6 and CYP2C19
132
What are the consequences of CYP2D6 metabolic phenotypes on SSRIs?
UM metabolizers for CYP2D6 for SSRIs will result in lower plasma levels of the drug therefore resulting in therapy failure while PM for CYP2D6 will have higher plasma concentrations of the SSRIs and have a higher likelihood of side effects.
133
How is the TCA drug amitriptyline metabolized?
Amitriptyline itself is active and it selective for serotonergic neurons. It can be converted to another active molecule called nortriptyline by CYP2C19 which is more selective for NE neurons. Amitriptyline can also be converted to inactive by CYP2D6.
134
What are the consequences of CYP2D6 metabolic phenotypes on TCAs?
UM metabolizers for CYP2D6 will not have enough active drug in their system as it will take most of the amitriptyline and make it inactive. This will make the therapy fail.
135
What are the consequences of CYP2C19 metabolic phenotypes on SSRIs?
UM metabolizers for CYP2C19 will have lower plasma concentrations of the SSRIs which may result in therapy failure. PM metabolizers for CYP2C19 result in higher plasma concentrations of SSRIs which may result in more side effects.
136
What are the consequences of CYP2C19 metabolic phenotypes on TCAs?
Remember that CYP2C19 converts active amitriptyline to active nortriptyline. UM metabolizers for CYP2C19 have increased metabolism into the nortriptyline which may alter the effect of the drug and unwanted side effects as it is more selective for NE neurons. PM metabolizers for CYP2C19 will basically block the conversion of active amitriptyline to nortriptyline which will allow for of the amitriptyline to act on serotonergic neurons.
137
T or F: CPIC recommends individuals who are CYP2C19 poor metabolizers (PM) consider alternative SSRIs due an increased risk of therapy failure (i.e., decreased activity and efficacy).
False
138
What is 6-mercaptopurine?
This is a thiopurine cytotoxic prodrug that is an immunosuppressant that acts as a purine antagonist. It looks like NTs and can get put into DNA when leukemia cancer cells are replicating and stall the replication and then kill them.
139
What are the key interactions between TPMT and 6-mercaptopurine?
There are 3 pathways that alter 6-mercaptopurine. Only 1 pathway makes it active. The TPMT pathways activates the deactivating S-methylation to make it inactive. If this drug enters the TPMT pathway, there is less prodrug that can be made active by other enzymes.
140
How do TPMT variants impact 6-mercaptopurine metabolism, active metabolite levels (TGN), and toxicity?
One or two TPMT variants show decreased metabolic inactivation of the prodrug 6-mercaptopurine which leaves more prodrug to be converted into its active form called TGN. Overall, those with this mutation will need less of the drug.
141
What is a common side effect for those with two copies of the mutated TPMT?
This would result in high levels of the active 6-mercaptopurine metabolite called TGN which can lead to myelosuppression.
142
What is the chromosomal alteration that causes BCR-ABL fusion?
Translocation of chromosome 9 and 22 and caused chronic myeloid leukemia (CML).
143
How does imatinib target BCR-ABL?
Imatinib binds to the ATP/ADP binding pocket of the BCR-ABL which shuts of the overactivity of the protein and turns it off. It prevents the kinase activity to stop downstream signalling.
144
How does BCR-ABL develop resistance to imatinib?
Cancer cells are able to sense when there is a drug stopping them so they will mutate to figure out a way to stop being inhibited. The mutations in the BCR-ABL stop imatinib from binding to the ATP/ADP site. It is typically due to secondary mutations that stop imatinib from working.
145
What does vismodegib target in the SHH signaling pathway?
Vismodegib is a SMO antagonist that stops the constant cellular proliferation signalling of Sonic Hedgehog Pathway. This works in cells that have their mutation at the PTCH1 site which would normally negative feedback and stop SMO.
146
Why are some SHH medulloblastomas sensitive to vismodegib and some are resistant?
Some sonic hedgehog pathway medulloblastomas are resistant as their tumors do not have PTCH1 mutations. It is likely that something else within the pathway is mutated so vismodegib does not work.
147
What are the components of CRISPR-Cas9 and what do they do?
1. Single guide RNA (sgRNA)- short sequence of RNA that is complementary to the sequence of DNA you want to target
2. Cas9 protein- binds sgRNA and locates the specific sequence on DNA. Cas9 then cuts the double stranded DNA and cause the alterations. Once cut, the cell itself tries to fix to damage
148
What is the pathophysiology surrounding sickle cell anemia?
The onset of SCA is associated with the transition from fetal to adult hemoglobin. Fetal hemoglobin has aa/ff while adult had aa/bb. The switch is driven by repression of fetal hemoglobin by the transcription factor BCL11A. Upon deoxygenation, the sickle cell variant can polymerize and cause the RBCs to become sickle shaped.
149
How is BCL11A gene related to sickle cell anemia?
BCL11A is a transcription factor that switches us from fetal to adult hemoglobin. It was found that those with a SNP in the BCL11A had more fetal hemoglobin and had more mild sickle cell anemia.
150
How is CRISPR-Cas9 being used to treat the sickle cell anemia?
Hematopoietic stem cells are taken from the patient and CRISPR-Cas9 is used to edit the BCL11A enhancer. This will decrease the BCL11A expression and increase fetal hemoglobin expression. The stem cells are given back to the patient.
151
What gene is the CRISPR-Cas9 therapy targeting and why does it work to restore hemoglobin function?
It targets BCL11A which represses fetal hemoglobin, restoration of fetal hemoglobin expression, which restores overall hemoglobin function.
152
How is CRISPR-Cas9 being used to target HIV?
gRNAs made to target integrated HIV regions on human DNA. Cas9 will cut the viral DNA out. The body will fix the damage and the HIV is no longer integrated into the host genome and will no longer be able to replicate itself.
153
How does someone find different genetic tests to take?
GTR website
154
How are genetic tests regulated by the government?
FDA regulates the physical test but not how the test is interpreted.
155
Humans usually have 23 pairs of _________.
Chromosomes
156
The main focus of the Clinical Pharmacogenetics Implementation Consortium (CPIC) is to provide guidance on what?
What to do with the genetic testing information
157
T or F: Disorders caused by Y-linked genetic variants can be passed on from fathers to sons.
True
158
This term refers to the set/pair of alleles for a particular gene or locus:
a. Phenotype
b. Genotype
c. Basetype
d. INDEL
B. Genotype
159
Used to describe alternative forms of a gene at a given locus
a. Chromosome
b. Phenotype
c. Genotype
d. Allele
D. Allele
160
In coding regions of the genome, a synonymous SNP results in...
A. A change in the AA sequence
B. No change in the AA sequence
C. Gene deletion
D. Non-functional protein
B. No change in the AA sequence
161
Copy number variants (CNVs) refer to:
A) A deletion or duplication of segments in the genome
B) Single base pair changes in a gene
C) Changes only in noncoding regions of a gene
D) None of the above
A. A deletion or duplication of segments in the genome
162
T or F: patients who harbor deficient variants in G6PD should avoid Rasburicase treatment due to lack of efficacy.
False.
163
Which of the following is a pharmacodynamic factor influenced by genetic variation?
A) Drug absorption
B) Drug distribution
C) Drug target modification
D) Drug elimination
C. Drug target modification
164
Why are G6PD-deficient individuals at risk when exposed to fava beans or certain drugs?
A) They lack immune response to pathogens
B) They have reduced ability to manage oxidative stress
C) They cannot absorb vitamins properly
D) They metabolize drugs too quickly
B. They have reduced ability to manage oxidative stress
165
Which genotyping technique involves hybridization of fluorescently labeled DNA fragments to a gene chip?
A) Sanger sequencing
B) PCR
C) DNA microarray
D) Next-generation sequencing
C. DNA microarray
166
T or F: Genome wide association studies (GWAS) do not require a defined candidate allele but do require the use of well-defined cohorts of subjects with and without a qualitative trait being studied.
True
167
This is NOT a part of the Next-Generation Sequencing process:
a. Bridge amplification
b. Library preparation
c. Data alignment
d. Agarose gel separation
D. Agare gel seperation
168
This CYP gene is non-inducible, and genetic variation is a large contributor of inter-individual enzyme activity:
a. CYP2D6
b. CYP2D9
c. CYP2C19
d. CYP2C9
A. CYP2D6
169
An individual with the CYP2D6 *1 / *1 genotype would be predicted to be what metabolizer phenotype?
a. Poor Metabolizer
b. Intermediate Metabolizer
c. Extensive Metabolizer
d. Ultra-rapid Metabolizer
C. Extensive metabolizer
170
What is the role of primers in PCR?
A) To cleave DNA strands
B) To bind to specific sequences in the DNA
C) To add nucleotides to the DNA
D) To measure DNA concentration
B. To bind to specific sequences in the DNA
171
Ultra-rapid metabolizers are usually associated with activity scores of:
a. 0
b. < 1
c. 2
d. > 2
D. >2
172
An individual is genotyped as CYP2C9 *3 / *3 (PM; Poor Metabolizer). If given a standard dose of the NSAID celecoxib, you would predict:
a. Increased celecoxib levels
b. Decreased celecoxib levels
c. No changes in celecoxib levels
d. Decreased risk of toxicity
A. Increased celecoxib levels
173
T or F: An individual genotyped as a NAT2 slow acetylator phenotype should be given a lower dose of INH due to increased risk of toxicity at standard INH dosing
True
174
T or F: CPIC guidelines recommend UGT1A1 poor metabolizers consider an alternative medicine to atazanavir, as it can inhibit their remaining UGT1A1 enzyme activity and increase the likelihood
of developing jaundice.
True
175
What is the clinical impact of MT-RNR1 genetic variants in patients treated with
aminoglycosides?
a. Increased risk of hearing loss
b. Enhanced antibacterial efficacy
c. Increased risk of HIV infection
d. Reduced drug metabolism
A. Increased risk of hearing loss
176
The ABC transporter family utilizes ________ to pump substances out of cells.
a. ATP energy
b. Facilitative energy
c. Calcium gradients
d. Diffusion gradients
A. ATP energy
177
SLCO1B1 genetic variants alter statin pharmacokinetics by acting directly on statin:
a. Metabolism
b. Target binding
c. Transport into the liver
d. Transport out of the liver
C. Transport into the liver
178
ABC and SLC transporter families are mainly associated with _______ and _______
transporters respectively.
a. Influx and Efflux
b. Passive and Active
c. Efflux and Influx
d. Influx and Active
C. Efflux and Influx
179
T or F: SLC family transporters cannot transport substrates against concentration gradients.
False
180
Tezacaftor is classified as a CFTR _________ therapy.
a. Corrector
b. Potentiator
c. Inhibitor
d. Degrader
A. Corrector
181
CFTR alleles classified as class III (3) variants (i.e. G551D) generate CFTR protein that:
a. is truncated
b. is misfolded and degraded in the cell
c. is not stable
d. makes it to the cell surface, but is not functional
D. Makes it to the cell surface, but it is not functional
182
The BCR-ABL fusion results from a chromosomal alteration involving the exchange of segments between Chr9 and Chr22. This type of alteration is termed:
a. Inversion
b. INDEL
c. Transcription
d. Translocation
D. Translocation
183
T or F: A leukemia patient with poor TPMT metabolic activity likely requires a higher dose of 6-mercaptopurine to achieve optimal efficacy.
False
184
Vismodegib is a SHH antagonist that binds to and inhibits this protein:
a. PTCH1
b. SMO
c. SUFU
d. GLI2
B. SMO
185
In the CRISPR-Cas9 system, this component is the enzyme that cuts DNA to create double strand breaks.
a. sgRNA
b. CRISPR
c. Cas9
d. PAM
C. Cas9
186
Currently used CRISPR-Cas9 gene editing therapies directly target this gene enhancer in patients with sickle cell disease.
a. HBB
b. HBA
c. BCL11A
d. CAS9
C. BCL11A
187
A patient’s PGx testing results come back with the genotype CYP2D6 *1/*3. The CYP2D6 *3 allele encodes for a non-functional protein variant. What would be the patient’s predicted activity score for the CYP2D6 *1/*3 genotype?
0, 1, 2, or 3?
1
188
Which CYP2D6 metabolic phenotype results in increased morphine levels and a higher risk of toxicity when taking codeine?
A. Poor metabolizer (PM)
B. Extensive metabolizer (EM)
C. Ultra-rapid metabolizer (UM)
D. Intermediate metabolizer (IM)
C. Ultra-rapid metabolizer
189
Following administration of a standard dose, you would predict to find the lowest omeprazole (OME) plasma levels in an individual with which CYP2C19 metabolic phenotype?
A. CYP2C19 UM
B. CYP2C19 EM
C. CYP2C19 IM
D. CYP2C19 PM
A. CYP2C19 UM
190
T or F: CFTR alleles classified as class II (2) variants (i.e., F508del) generate CFTR protein that is misfolded in the endoplasmic reticulum and targeted for degradation.
True
191
T or F: An individual that is homozygous for reduced function SLCO1B1 alleles (i.e., SLCO1B1*5/*5) should avoid using simvastatin due to decreased therapeutic efficacy.
False. They should avoid it due to risk of toxicity like SAMS not due to decreased efficacy.
192
Warfarin levels and efficacy is influence by genetic variation in CYP2C9 and VKORC1. These genetic variants influence warfarin ________ and _________ respectively.
A. Pharmacodynamics and Transport
B. Pharmacokinetics and Metabolism
C. Pharmacokinetics and Pharmacodynamics
D. Pharmacodynamics and Pharmacokinetics
C. PK and PD
193
T or F: CPIC recommends individuals who are CYP2C19 poor metabolizers (PM) consider alternative SSRIs other than Citalopram and Sertraline due to higher plasma concentrations and increased risk of adverse events / side effects compared to CYP2C19 extensive metabolizers (EM)
True
194
T or F: CYP2C19*2 and *3 alleles result in truncated, non-functional proteins. An individual is genotyped as CYP2C19*2/*3. You would predict reduced efficacy of the antiplatelet drug clopidogrel compared to someone who was genotyped as CYP2C19*1/*1.
True
