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Flashcards in Exam 1 Deck (164):
1

What is the null hypothesis?

There is no association between alleles and phenotype

2

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

Small

3

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

<0.05

4

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

5x10(^-8)

5

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

Accept

6

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

FALSE

7

T/F: Odds ratio measures strength of association

TRUE

8

What is the Odds Ratio?

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

9

What does OR =1 mean?

No association

10

What does OR > 1 mean?

Allele is associated with Increased Risk

11

What does OR<1 mean?

Allele is associated with decreased risk (protective allele)

12

95% CI >1:

Statistically significant increase in risk

13

95% CI including 1

No statistically significnat difference

14

95% CI <1

Statistically significant decrease in risk (protective effect)

15

What is LEM caused by?

GOF in Nav1.7

16

What does LOF in Nav1.7 cause?

Insensitivity to pain

17

What alleles can be treated with CBZ?

V400M
S241T
NOT F1499

18

What is MEA?

A way to measure action potentials without dilating cell

19

What is iPSC?

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

20

What is the most common CYP?

CYP3A

21

What are the CYP2D6 variants?

*1: Normal
*9, *10: Reduced
*3-*6: No function

22

What is the clinical significance of CYP2D6?

Codeine
Hydrocodone
Nortriptyline
Fluoxetine
Metoprolol
Carvedilol
Tramadol

23

What are the CYP2C9 variants?

*1: WT
*2, *3: Low function

24

What drugs are affected by CYP2C9

A LOT--including warfarin, phenytoin, tolbutamide, glipizide

25

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

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

26

CYP2C19 variants?

*1: Normal
*2/*3: Reduced
*17: Ultrarapid

27

What is the clinical relevance of CYP2C19?

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

28

What are the variants of CYP3A4

*22--reduced function

29

What are the variants of CYP3A5

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

30

What is the clinical significance of CYP3A4/5

Tacrolimus, cyclosporine, simvastatin

31

Are CYPs Phase I or Phase II?

Phase I

32

Are UGTs Phase I or Phase II?

Phase II

33

What are the UGT families?

1,2,3,8

34

What do UGTs do?

Conjugate enzymes -- transfer glucuronic acid to substrate

35

What is the UGT1A1 variant?

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

36

UGT1A9's most studied variant?

*9--reduced function

37

UGT1A9 clinical significance?

Mycophenolic acid
Irinotecan
Raltegravir
(all increased exposure)

38

TPMT variants

*1: normal
*N: Heterozygous

39

What does TPMT variant increase the concentration of?

TGN

40

What does increased TGN lead to?

Neutropenia!!

41

What drugs are affected by TMPT?

6-Mercaptopurine
Azathioprine
Thioguanine

42

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

10-fold! and only give 3 times a week

43

What drugs with NAT?

Isoniazid**
Hydralazine
Dapsone
Sulfonamides**
Caffeine

44

Variants of NAT?

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

45

Where is OATP1B1 found?

Liver

46

What does SLCO1B1 code for?

OATP1B1

47

What does decreased OATP1B1 do?

Decrease metabolism/excretion
Increase systemic circulation

48

What are variants of SLCO1B1?

*1:WT
*5,*17: Low
*15: real low

49

Clinical relevance of SLCO1B1?

Statin myopathy
(esp simvastatin)
Also reduces efficacy

50

What does decreased PGP efficacy do?

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

51

What is BCRP?

Efflux transporter in gut and liver

52

Clinical significance of BCRP?

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

53

What does OCT1 do?

Hepatic uptake of drugs into the liver

54

What drugs are affected by OCT1?

Metformin - reduces efficacy but increases plasma concentrations

55

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

Hypertension
Diuretics

56

What disease do Prothrombin and Factor V cause?
Associated with what drug class?

DVT and thrombosis
Oral contraceptives

57

What disease does Apolipoprotein E contribute to?

Alzheimer's and atherosclerosis

58

What drugs are used to treat atherosclerosis with APOE polymorphism?

Statins

59

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

Tacrine

60

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

Atherosclerosis
Statins--pravastatin

61

G6PD deficiency can cause what ADR?

Favism/hemolytic anemia

62

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

Fatal skin reactions in Asians
Carbamazepine

63

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

Immunological ADRs--rash, fever, GI/respiratory distress
Abacavir

64

Bradykinin B2 receptor causes what ADR? What drug?

ACE Inhibitor--cough

65

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

Hyperthermia
Volatile anesthetics

66

Mutated cardiac ion channels cause what ADR?

QT Prolongation and TdP

67

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

Gly16 allele in Beta2 receptors (ADRB2)

68

What are microRNAs?

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

69

What direction is DNA read?

5' --> 3'

70

What project allowed development of a reference genome?

Human Genome Project

71

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

Locus

72

Which is unwound--chromsome or chromatin?

Chromatin

73

What is a karyotype?

The complete picture of a genome in a cell

74

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

True

75

T/F: DNA can be made from RNA

True

76

T/F: RNA can be made from protein

false

77

Where does mRNA maturation process occur?

In the nucleus

78

What happens during mRNA translation?

Poly-A tail added, introns removed

79

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

True

80

Translation starts with what codon?

AUG

81

What are the 3 stop codons?

UAG, UAA, UGA

82

Does the ORF include the stop codon?

No--stops at codon before

83

How many codon?

64

84

How many amino acids?

20

85

What is a polymorphism?

A sequene variation at the same position of HOMOLOGOUS CHROMOSOMES

86

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

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

87

What is a hemizygote?

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

88

What is Mendel's Law?

Parents pass randomly selected allele to offspring

89

What is the UGT1A1 polymorphism?

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

90

What's the difference btween
c.1297 G>A and p.Val433Met

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

91

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

Splicing defect

92

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

Nonsense

93

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

missense

94

Whay CYP2C19 are intermediate metabolizers?

*1/*2, *1/*3, *2/*17

95

What CYP2C19 are extensive metabolizers?

*1/*1

96

What is MAF?

Minor allele frequency--percent of less common allele

97

What is a haplotype?

A group of genes inherited together from single parent
Inheritance of a cluster of SNPs (together)

98

What is linkage disequilibrium?

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

99

If two SNPs are really close, LD = ?

1

100

If two SNPs are rally far, LD = ?

0

101

What is R2?

a measure of correlation b/w two variables

102

What R2 is considered strong LD

>0.8

103

What is a tagSNP?

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

104

What is the Human genome project's goal?

Complete mapping/understanding of all genes of human beings
-Map a reference genome

105

What is the HapMap Project?

continued study from HGP--studies in DNA variation

106

What are the benefits from HPG?

a REFERENCE SEQUENCE! - powerful tool for research

107

What is the HapMap Project goal?

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

108

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

Africans

109

What has replaced HapMap?

1000 Genome project

110

What's the goal of the 1000 Genome Project?

Identify variants with frequencies of at least 1%

111

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

Ensembl GRCH38

112

What is 1st pharmacogenetic resource?

PharmGKB

113

What are CPIC Guidelines?

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

114

Which CYP2C9 variants are more important for African American?

5-11

115

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

Patients with chemo
Bone marrow transplant patients

116

What type of tube for blood cell DNA collecting?

EDTA-anticoagulant tube

117

What are limitations of cheek swabbing for DNA?

-Less DNA yield
-Possible contaminations

118

When do you take tissue samples for DNA?

Tumors
(use dry ice for transportation of fresh biopsy)

119

What temperature can DNA be stored at short term?

4C

120

What temperature can DNA be stored at long term?

-80C

121

What process is used for DNA amplification?

PCR

122

How does PCR work?

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

123

What are the steps for PCR?

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

124

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

2^(N+1)
N = cycles

125

Does PCR amplify both chromosomes?

yep--both homologous chromosomes
Ned more tech to identify specific alleles

126

DNA Chip: known or unknown SNPs?

Known

127

DNA Chip: High throughput or low throughput?

high

128

DNA Chip: Cost?

Medium cost, low per SNP

129

What is Amplichip CYP450 Array?

Chip-based Pgx teting platform, FDA-approved by Roche
Used for CYP2D6 and CYP2C19

130

What are the 2 sequecning methods?

Sanger
next generation sequencing

131

Sanger: high or low throughput?

Low

132

Sanger: Targeted or not?

Targeted

133

Next generation sequencing: High or low throughput?

High

134

Next generation sequncing: target or not?

not

135

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

chain-terminating dideoxynucleotides

136

What type of DNA sequencing method relies on PCR amplification?

Sanger sequencing

137

How does NGS sequence?

By synthesis--builds the DNA and lights up depending on what's added

138

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

10 to 30x

139

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

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

140

What is karyotyping used to detect?

chromosomal rearrangement (Philadelphia chromosomes)

141

What act limited data sharing from genetic issues?

GINA - Genetic Information Non-Discrimination Act

142

How can CYP2D6 be ultrarapid?

CNV - more copies of normal functioning gene

143

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

NF: 3-6
Reduced function: 9-10

144

Which drug is a prodrug of CYP2D6 ?

Codeine

145

CYP2C9 has what reduced function alleles?

*2, *3

146

Which CYP2C9 genotypes are intermediate? which are poor metabolizers?

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

147

*2/*17 CYP2C19 allele is what type of metabolizer?

Intermediate

148

CYP2C19 normal metabolizer?

*1 /*1

149

Which CYP3A5 alleles have LOF?

3, 7, 6

150

What raises of CYP3A5 present?

50% of African americansa
1/3 of hispanic and Asian

151

how do you change tacrolimus if someone has CYP3A5?

Increase starting dose 1.5-2x

152

UGT1A1 has what variant?

*28 - 7 copies of TA in TATA box

153

UGT1A9 has what variant?

*3 - reduced function

154

Substrates of TPMT?

Mercaptopurine
Azathioprine
Thioguanine

155

Variants of TPMT?

*1/N --- N means reduce dose
N/N means reduce dose A LOT

156

What is NAT reference allele?

*4

157

How is NAT grouped?

Slow - has a *4
Rapid - does not have a *4

158

What are intermediate SLC01B1 phenotypes?

1/5
1/17

159

What genes encode PGP?

ABCB1, MDR1

160

PGP affects what drug?

Digoxin

161

Reduced PGP function affects bioavailability how?

Increases--less efflux back into GI

162

Reduced PGP function affects hepatotoxicity how?

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

163

What gene encodes BCRP?

ABCP

164

What drugs are affected by BCRP polymorphisms?

Sulfasalazine
Rosuvastatin
Topotecan
Gefitinib