Exam 1 Flashcards
(100 cards)
1
Q
Clopidogrel gene of interest
A
CYP2C19
2
Q
Warfarin gene of interest
A
CYP2C9, VKORC1
3
Q
Statins gene of interest
A
SLCO1B1
4
Q
Phenytoin gene of interest
A
CYP2C9, HLA-B
5
Q
TCA/SSRI gene of interest
A
CYP2C19, CYP2D6
6
Q
Thiopurines gene of interest
A
TPMT
7
Q
Tacrolimus gene of interest
A
CYP3A5
8
Q
Atazanavir gene of interest
A
UGT1A1
9
Q
Pharmacogenomics definition
A
The study of whole genomic effects on drug response
10
Q
Pharmacogenetics definition
A
The study of individual gene-drug interactions
11
Q
How many nucleotide bases are in the Human Genome
A
3 billion
12
Q
How many nucleotide bases are in the average gene
A
3000
13
Q
Estimated total number of genes
A
20-30 thousand
14
Q
Reasons for a pharmacogenetic treatment
A
Improve efficacy, reduce toxicity, predict non-responders, and minimize the burden on the healthcare system
15
Q
Precision medicine definition
A
Tailored disease prevention and treatment taking into account differences in an individual’s genes, environment, and lifestyle
16
Q
Precision Therapeutics definition
A
Customizing medications to patients, categorized by molecular and cellular biomarkers in order to improve treatment outcomes
17
Q
Amount of variation between individuals’ genetic makeup
A
0.1-0.5%
18
Q
When did Mendel publish his work on inherited factors (genes)
A
1866
19
Q
When was DNA identified by Friedrich Miescher
A
1869
20
Q
When did Watson & Crick identify the structure of DNA
A
1953
21
Q
When did Vogel introduce the term pharmacogenomics
A
1959
22
Q
When did Marshal Nirenberg crack the genetic code for protein synthesis
A
1961
23
Q
When was DNA sequencing invented
A
1975
24
Q
When was PCR invented
A
1983
25
When was the Human Genome launched
1999
26
When was the Human Genome completed
2003
27
When was next generation sequencing developed
2007
28
When was Clinical Pharmacogenetics Implementation Consortium established
2009
29
When was personalized healthcare initiative announced
2015
30
Pharmacokinetics definition
What the body does to the drug (defines the exposure to a drug)
31
Pharmacodynamics definition
What the drug does to the body (defines drug effect)
32
Intrinsic variables
Pregnancy, race, organ function, lactation, sex, disease, age, genetics
33
Extrinsic variables
Drug-drug interaction, environment, diet, EtOH, Medical practice, smoking
34
What is drug response determined by
Genetics, disease, environment, lifestyle, concomitant drugs
35
What does genetic variation lead to
Changes in drug ADME
36
Enzyme variation results in
Activation or deactivation
37
Transporter variation results in
Absorption, distribution, or elimination rates
38
Receptor variation results in
Drug effect (pharmacodynamics)
39
Amount of prescription drugs in the US affected by actionable pharmacogenes
18%
40
Amount of FDA-approved medications affected by actionable pharmacogenes
7%
41
Possible outcomes of drug therapy
Effective with minimal toxicity, effective with toxicity, failure with minimal toxicity, failure with excessive toxicity
42
Textbook model: Genome
The book
43
Textbook model: Chromosome
The chapter
44
Textbook model: Gene
The sentence
45
Textbook model: Nucleotide
The letters
46
Chromosome definition
Cellular structures containing genes
47
Gene definition
A segment of DNA that contains information for making a protein or RNA molecule
48
Phenotype definition
The outward characteristic of an individual - the measurable trait
49
Synonymous SNP
No change in AA previously termed "silent" can alter mRNA stability. Does not change the AA.
50
Non-synonymous SNP
A nucleotide mutation that alters the AA sequence of a protein
51
Missense SNP
A change in one DNA base pair that results in the substitution of one AA for another in the protein made from a gene
52
Nonsense SNP
Insertion of a stop codon truncated incomplete, and usually, nonfunctional protein product --> inactive
53
CYP2B6*4A - CYP2
Family gene name
54
CYP2B6*4A - CYP2B
Subfamily gene name
55
CYP2B6*4A - CYP2B6
Enzyme gene name
56
CYP2B6*4A - 4
Allele
57
CYP2B6*4A - A
Suballele
58
Drug metabolizing enzymes normal/extensive metabolizer phenotype
Combination of normal function and decreased function alleles (fully functional enzyme)
59
Drug metabolizing enzymes intermediate metabolizer phenotype
Combination of normal function decreased function, and/or no function alleles (decreased enzyme activity)
60
Drug metabolizing enzymes poor metabolizer phenotype
Combination of decreased function and/or no function alleles (decreased or no enzyme activity)
61
Drug metabolizing enzymes rapid metabolizer phenotype
Combination of normal function and increased function alleles (increased enzyme activity)
62
Drug metabolizing enzymes ultra-rapid metabolizer phenotype
Combination of increased function alleles (increased enzyme activity)
63
What offers genotype-based guidance for drug dosing
Clinical pharmacogenetics implementation consortium (CPIC)
64
What offers PGx knowledge base (literature, annotation guidance)
PharmGKB
65
What offers nomenclature resource
PharmVar - Pharmacogene variation concortium
66
What offers PGx clinical annotation tool
PharmCat
67
Goal of CPIC
Address the barrier to clinical implementation of PGx tests by creating, curating, and posting freely available, peer-reviewed, evidence-based, updateable, and detailed gene/drug clinical practice guidelines
68
CPIC grading system - gene/drug pair Rx actionability
A - D
69
CPIC grading system - Guideline Rx recommendation
Strong, moderate, optional, none
70
Diplotype definition
Results of a PGx that includes one maternal and one paternal allele
71
Prodrug slow metabolizer
Poor efficacy
72
Prodrug rapid metabolizer
Good efficacy, rapid effect
73
Active drug slow metabolizer
Good efficacy, accumulation of drug
74
Active drug rapid metabolizer
Poor efficacy
75
CPIC key assumption
Genotyping will become more widespread where all patients will get PGx tested
76
Anticoag for CYP2C19: *1/*17, 17*/17, *1/*1
Clopidogrel standard dose
77
Anticoag for CYP2C19: *1/*2, *1/*3, *2/*17, *2/*2, *2/*3, *3/*3
Alternative (prasugrel, ticegrelor)
78
`Anticoag for CYP2C19 UM/RM, NM
Clopidogrel standard dose
79
Anticoag for CYP2C19 IM, PM
Alternative (prasugrel, ticegrelor)
80
Pharmacist's responsibilities in PGx
Educate patient about PGx principles
Advocate for rational and routine use of PGx testing
81
Elements of a basic understanding of PGx should enable pharmacists to
Recommend PGx testing to aid in drug and dose selection
Design a patient-specific medication regimen based on a patients profile
Educate patients and other healthcare providers on the principles of PGx and indications for testing
Communicate PGx-specific medication recommendations to the healthcare team
82
PGx online database: PharmGKB detail
Robust: Rx information, drug label, variant, and clinical annotations. Provides links to guidelines
83
Clinical Practice Guidelines detail
Published annually, worldwide acceptance. Do not advise on who to test, aid in "what to do" with the results of PGx
84
FDA recourse details
Limited: dated material, lack of clinical utility, interpretation by clinician necessary
85
Sanger sequencing
Chain termination method. Needs the whole sequence - PCR with radioactive dideoxynucleotides, then gell electrophoresis to separate PCR, then decode the sequence of interest
86
Sanger sequencing benefits
Conformation of variants
Detects rare or novel SNPs
87
Sanger sequencing limitations
Low throughput
Not targeted
88
Next generation sequencing
The standard in clinical dx and research
Pyrosequencing, ion semiconductor sequencing (pH based), and dye sequencing (by ligation) - SOLiD
89
Next generation sequencing benefits
High throughput
Detects rare or novel SNPs
Able to be targeted
90
Next generation sequencing limitations
Higher cost
More sophisticated
Informatics needed
91
Allelic discrimination and detection method
Mostly PCR-based
Discrimination: primer extension, hybridization, ligation, enzymatic cleavage
Detection: Mass spectrometry, fluorescence, chemiluminescence
92
qPCR benefits
Low cost
High throughput
93
qPCR limitation
Small # of SNPs/genes
Small # of samples
Known varients only
94
Microarray/chip benefits
Low cost
High throughput
Many SNPs/genes
95
Microarray/chip limitations
Known variants only
Small # of samples
96
What certification is required for clinical labs
Clinical Laboratory Improvement Amendments
97
Which PGx method would be best to identify a patient's CYP2C19 status to guide clopidogrel tx
Quantitative PCR
98
GINA
Genetic Information Nondisclosure Act
99
GINA definition
Title I: protects individuals against genetic discrimination with respect to health insurance
Title II: Protects individuals against employment discrimination on the basis of genetic information
- employers are prohibited from requesting, requiring, or purchasing genetic information about applicants or employees
- employers prohibited from using genetic information for pay, promotion or job assignments
100
What does whole exome sequencing not identify
Regulatory and intronic variants
