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Pharmacogenomics > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

What is the null hypothesis?

A

There is no association between alleles and phenotype

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2
Q

Does a large or small Chi Square support the null hypothesis?

A

Small

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3
Q

What p-value is used for an association if only a specific SNP is being tested?

A

<0.05

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4
Q

What p-value is used if Genome-Wide Association Study is used?

A

5x10(^-8)

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5
Q

A high p-value means you (accept/reject) null hypothesis

A

Accept

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6
Q

T/F: A p-value measures the strength of association

A

FALSE

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7
Q

T/F: Odds ratio measures strength of association

A

TRUE

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8
Q

What is the Odds Ratio?

A

Odds of phenotype in individual with the genotype/odds of phenotype in individual without genotype

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9
Q

What does OR =1 mean?

A

No association

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10
Q

What does OR > 1 mean?

A

Allele is associated with Increased Risk

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11
Q

What does OR<1 mean?

A

Allele is associated with decreased risk (protective allele)

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12
Q

95% CI >1:

A

Statistically significant increase in risk

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13
Q

95% CI including 1

A

No statistically significnat difference

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14
Q

95% CI <1

A

Statistically significant decrease in risk (protective effect)

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15
Q

What is LEM caused by?

A

GOF in Nav1.7

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16
Q

What does LOF in Nav1.7 cause?

A

Insensitivity to pain

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17
Q

What alleles can be treated with CBZ?

A

V400M
S241T
NOT F1499

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18
Q

What is MEA?

A

A way to measure action potentials without dilating cell

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19
Q

What is iPSC?

A

Can make stem cells identical to host to test drugs on without exposing patient to them

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20
Q

What is the most common CYP?

A

CYP3A

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21
Q

What are the CYP2D6 variants?

A
  • 1: Normal
  • 9, *10: Reduced
  • 3-*6: No function
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22
Q

What is the clinical significance of CYP2D6?

A 
Codeine
Hydrocodone
Nortriptyline
Fluoxetine
Metoprolol
Carvedilol
Tramadol
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23
Q

What are the CYP2C9 variants?

A
  • 1: WT

* 2, *3: Low function

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24
Q

What drugs are affected by CYP2C9

A

A LOT–including warfarin, phenytoin, tolbutamide, glipizide

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25
Q

T/F: All drugs are affected the same by CYP2C9

A

FALSE: Do not assume clinical significance unless studies have shown it

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26
Q

CYP2C19 variants?

A
  • 1: Normal
  • 2/*3: Reduced
  • 17: Ultrarapid
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27
Q

What is the clinical relevance of CYP2C19?

A

Clopidogrel (increases activity because PRODRUG)
Omeprazole
Antidepressants (citalopram, escitalopram, sertraline)
Voriconazole

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28
Q

What are the variants of CYP3A4

A

*22–reduced function

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29
Q

What are the variants of CYP3A5

A

1–increased activity
6,7,3–null function
(*3 is NORMAL)

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30
Q

What is the clinical significance of CYP3A4/5

A

Tacrolimus, cyclosporine, simvastatin

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31
Q

Are CYPs Phase I or Phase II?

A

Phase I

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32
Q

Are UGTs Phase I or Phase II?

A

Phase II

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33
Q

What are the UGT families?

A

1,2,3,8

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34
Q

What do UGTs do?

A

Conjugate enzymes – transfer glucuronic acid to substrate

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35
Q

What is the UGT1A1 variant?

A

*28–decreased function (an extra TA in TATA box)

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36
Q

UGT1A9’s most studied variant?

A

*9–reduced function

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37
Q

UGT1A9 clinical significance?

A

Mycophenolic acid
Irinotecan
Raltegravir
(all increased exposure)

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38
Q

TPMT variants

A
  • 1: normal

* N: Heterozygous

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39
Q

What does TPMT variant increase the concentration of?

A

TGN

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40
Q

What does increased TGN lead to?

A

Neutropenia!!

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41
Q

What drugs are affected by TMPT?

A

6-Mercaptopurine
Azathioprine
Thioguanine

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42
Q

In homozygous variant for TMPT, decrease dose of drugs by how much?

A

10-fold! and only give 3 times a week

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43
Q

What drugs with NAT?

A 
Isoniazid**
Hydralazine
Dapsone
Sulfonamides**
Caffeine
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44
Q

Variants of NAT?

A

*4: Reference
Not any 4s: SLOW
Containing a 4: Rapid

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45
Q

Where is OATP1B1 found?

A

Liver

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46
Q

What does SLCO1B1 code for?

A

OATP1B1

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47
Q

What does decreased OATP1B1 do?

A

Decrease metabolism/excretion

Increase systemic circulation

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48
Q

What are variants of SLCO1B1?

A
  • 1:WT
  • 5,*17: Low
  • 15: real low
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49
Q

Clinical relevance of SLCO1B1?

A

Statin myopathy
(esp simvastatin)
Also reduces efficacy

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50
Q

What does decreased PGP efficacy do?

A 
Increase bioavailability (prevents re-efflux into intestinal lumen)
Increase hepatocyte exposure (prevents excretion to bile)
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51
Q

What is BCRP?

A

Efflux transporter in gut and liver

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52
Q

Clinical significance of BCRP?

A

Increased exposure to sulfasalazine, rosuvastatin, topotecan, gefitnib (NOT irinotecan or pravastatin)

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53
Q

What does OCT1 do?

A

Hepatic uptake of drugs into the liver

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54
Q

What drugs are affected by OCT1?

A

Metformin - reduces efficacy but increases plasma concentrations

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55
Q 
What disease does adducin cause?
What drug class can be effective in treating?
A

Hypertension

Diuretics

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56
Q

What disease do Prothrombin and Factor V cause?

Associated with what drug class?

A

DVT and thrombosis

Oral contraceptives

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57
Q

What disease does Apolipoprotein E contribute to?

A

Alzheimer’s and atherosclerosis

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58
Q

What drugs are used to treat atherosclerosis with APOE polymorphism?

A

Statins

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59
Q

What drug is used to treat Alzheimer’s with APOE polymorophism?

A

Tacrine

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60
Q

What disease is caused by Cholesterol ester transfer protein?
What drug can slow progression?

A

Atherosclerosis

Statins–pravastatin

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61
Q

G6PD deficiency can cause what ADR?

A

Favism/hemolytic anemia

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62
Q

HLA-B*1502 mutation causes what ADR? In what population?

What drug?

A

Fatal skin reactions in Asians

Carbamazepine

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63
Q

HLA-B*5701 mutation causes what ADR? What drug?

A

Immunological ADRs–rash, fever, GI/respiratory distress

Abacavir

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64
Q

Bradykinin B2 receptor causes what ADR? What drug?

A

ACE Inhibitor–cough

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65
Q

DHP receptor Ca channel mutations cause what ADR? What drug?

A

Hyperthermia

Volatile anesthetics

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66
Q

Mutated cardiac ion channels cause what ADR?

A

QT Prolongation and TdP

67
Q

What mutation in what receptor is associated with more severe asthma?

A

Gly16 allele in Beta2 receptors (ADRB2)

68
Q

What are microRNAs?

A

Noncoding genes, play important role in regulating protein-coding gene expression

69
Q

What direction is DNA read?

A

5’ –> 3’

70
Q

What project allowed development of a reference genome?

A

Human Genome Project

71
Q

What is the position of each nucleotide within the reference genome called?

A

Locus

72
Q

Which is unwound–chromsome or chromatin?

A

Chromatin

73
Q

What is a karyotype?

A

The complete picture of a genome in a cell

74
Q

T/F: In all parts of the central dogma (DNA, RNA, protein), things can replicate themselves

A

True

75
Q

T/F: DNA can be made from RNA

A

True

76
Q

T/F: RNA can be made from protein

A

false

77
Q

Where does mRNA maturation process occur?

A

In the nucleus

78
Q

What happens during mRNA translation?

A

Poly-A tail added, introns removed

79
Q

T/F: There is a 5’UTR and a 3’UTR in matured mRNA

A

True

80
Q

Translation starts with what codon?

A

AUG

81
Q

What are the 3 stop codons?

A

UAG, UAA, UGA

82
Q

Does the ORF include the stop codon?

A

No–stops at codon before

83
Q

How many codon?

A

64

84
Q

How many amino acids?

A

20

85
Q

What is a polymorphism?

A

A sequene variation at the same position of HOMOLOGOUS CHROMOSOMES

86
Q

Are there polymorphisms in the genome of a signle germ cell?

A

No it is haploid, so doesn’t have homologous chromosomes

87
Q

What is a hemizygote?

A

one allele is present, the other is missing (type of heterozygousness)

88
Q

What is Mendel’s Law?

A

Parents pass randomly selected allele to offspring

89
Q

What is the UGT1A1 polymorphism?

A

Number of TATA boxes in promoter
6 or 7 are common
7 –> reduced gene expression

90
Q

What’s the difference btween

c.1297 G>A and p.Val433Met

A

c: in coding region, count nucleotides
p: protein position, count amino acids

91
Q

CYP2C19*2D - Missense, nonsense, splicing defect, indel?

A

Splicing defect

92
Q

CYP2C19*3A - Missense, nonsense, splicing defect, indel?

A

Nonsense

93
Q

CYP2C19*17 - Missense, nonsense, splicing defect, indel?

A

missense

94
Q

Whay CYP2C19 are intermediate metabolizers?

A

1/2, 1/3, 2/17

95
Q

What CYP2C19 are extensive metabolizers?

A

1/1

96
Q

What is MAF?

A

Minor allele frequency–percent of less common allele

97
Q

What is a haplotype?

A

A group of genes inherited together from single parent

Inheritance of a cluster of SNPs (together)

98
Q

What is linkage disequilibrium?

A

Non-random association of genes at different loci on the same chromosome (things closer together are inherited together more often)

99
Q

If two SNPs are really close, LD = ?

A

1

100
Q

If two SNPs are rally far, LD = ?

A

0

101
Q

What is R2?

A

a measure of correlation b/w two variables

102
Q

What R2 is considered strong LD

A

> 0.8

103
Q

What is a tagSNP?

A

A SNP representative of other SNps due to strong LD with them

104
Q

What is the Human genome project’s goal?

A

Complete mapping/understanding of all genes of human beings

-Map a reference genome

105
Q

What is the HapMap Project?

A

continued study from HGP–studies in DNA variation

106
Q

What are the benefits from HPG?

A

a REFERENCE SEQUENCE! - powerful tool for research

107
Q

What is the HapMap Project goal?

A 
to ID sequence variations among
Caucasians
Africans
east Asians
(ID SNPs/tagSNPs in haplotypes)
108
Q

Which population has most polymorphisms found in other populations accoring to HapMap?

A

Africans

109
Q

What has replaced HapMap?

A

1000 Genome project

110
Q

What’s the goal of the 1000 Genome Project?

A

Identify variants with frequencies of at least 1%

111
Q

What provides a genome browser to view 1000 Genomes Project on current reference genome?

A

Ensembl GRCH38

112
Q

What is 1st pharmacogenetic resource?

A

PharmGKB

113
Q

What are CPIC Guidelines?

A

Clinical Pharmacogenetics Implementation Consortium (tells you how genetic variations should influence treatment)

114
Q

Which CYP2C9 variants are more important for African American?

A

5-11

115
Q

Peripheral blood as DNA sample - special patients to not use in?

A

Patients with chemo

Bone marrow transplant patients

116
Q

What type of tube for blood cell DNA collecting?

A

EDTA-anticoagulant tube

117
Q

What are limitations of cheek swabbing for DNA?

A
  • Less DNA yield

- Possible contaminations

118
Q

When do you take tissue samples for DNA?

A

Tumors

use dry ice for transportation of fresh biopsy

119
Q

What temperature can DNA be stored at short term?

A

4C

120
Q

What temperature can DNA be stored at long term?

A

-80C

121
Q

What process is used for DNA amplification?

A

PCR

122
Q

How does PCR work?

A

Amplifies a specific region from the genome to make billions of copies so it is more detectable

123
Q

What are the steps for PCR?

A

Denaturation (temperature increased)
Annealing (temperature decreased)
Extension (polymerase extends)

124
Q

What is the total number of DNA at the end of PCR?

A

2^(N+1)

N = cycles

125
Q

Does PCR amplify both chromosomes?

A

yep–both homologous chromosomes

Ned more tech to identify specific alleles

126
Q

DNA Chip: known or unknown SNPs?

A

Known

127
Q

DNA Chip: High throughput or low throughput?

A

high

128
Q

DNA Chip: Cost?

A

Medium cost, low per SNP

129
Q

What is Amplichip CYP450 Array?

A

Chip-based Pgx teting platform, FDA-approved by Roche

Used for CYP2D6 and CYP2C19

130
Q

What are the 2 sequecning methods?

A

Sanger

next generation sequencing

131
Q

Sanger: high or low throughput?

A

Low

132
Q

Sanger: Targeted or not?

A

Targeted

133
Q

Next generation sequencing: High or low throughput?

A

High

134
Q

Next generation sequncing: target or not?

A

not

135
Q

Sanger sequencing is based on selective incorporation of ______ by DNA polymerase

A

chain-terminating dideoxynucleotides

136
Q

What type of DNA sequencing method relies on PCR amplification?

A

Sanger sequencing

137
Q

How does NGS sequence?

A

By synthesis–builds the DNA and lights up depending on what’s added

138
Q

What depth of coverage is recommended for human genome mutation detection? (How many times should each SNP be detected to count)

A

10 to 30x

139
Q

T/F: DNA chips are used for detecting somatic mutations

A

False: usually not used due to inaccurate readings for imbalanced mutant/wildtype copies

140
Q

What is karyotyping used to detect?

A

chromosomal rearrangement (Philadelphia chromosomes)

141
Q

What act limited data sharing from genetic issues?

A

GINA - Genetic Information Non-Discrimination Act

142
Q

How can CYP2D6 be ultrarapid?

A

CNV - more copies of normal functioning gene

143
Q

Which alleles for CYp2D6 are non-functional, which are reduced function?

A

NF: 3-6

Reduced function: 9-10

144
Q

Which drug is a prodrug of CYP2D6 ?

A

Codeine

145
Q

CYP2C9 has what reduced function alleles?

A

*2, *3

146
Q

Which CYP2C9 genotypes are intermediate? which are poor metabolizers?

A

Int: 1/2, *1/3
Poor: *2/2, *2/3, *3/3

147
Q

2/17 CYP2C19 allele is what type of metabolizer?

A

Intermediate

148
Q

CYP2C19 normal metabolizer?

A

1 /1

149
Q

Which CYP3A5 alleles have LOF?

A

3, 7, 6

150
Q

What raises of CYP3A5 present?

A

50% of African americansa

1/3 of hispanic and Asian

151
Q

how do you change tacrolimus if someone has CYP3A5?

A

Increase starting dose 1.5-2x

152
Q

UGT1A1 has what variant?

A

*28 - 7 copies of TA in TATA box

153
Q

UGT1A9 has what variant?

A

*3 - reduced function

154
Q

Substrates of TPMT?

A

Mercaptopurine
Azathioprine
Thioguanine

155
Q

Variants of TPMT?

A

*1/N — N means reduce dose

N/N means reduce dose A LOT

156
Q

What is NAT reference allele?

A

*4

157
Q

How is NAT grouped?

A

Slow - has a *4

Rapid - does not have a *4

158
Q

What are intermediate SLC01B1 phenotypes?

A

1/5

1/17

159
Q

What genes encode PGP?

A

ABCB1, MDR1

160
Q

PGP affects what drug?

A

Digoxin

161
Q

Reduced PGP function affects bioavailability how?

A

Increases–less efflux back into GI

162
Q

Reduced PGP function affects hepatotoxicity how?

A

Increases – less excretion into bile (so higher concentrations in liver)

163
Q

What gene encodes BCRP?

A

ABCP

164
Q

What drugs are affected by BCRP polymorphisms?

A

Sulfasalazine
Rosuvastatin
Topotecan
Gefitinib

Pharmacogenomics (3 decks)

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