Exam 1 Flashcards
1
Q
What is the null hypothesis?
A
There is no association between alleles and phenotype
2
Q
Does a large or small Chi Square support the null hypothesis?
A
Small
3
Q
What p-value is used for an association if only a specific SNP is being tested?
A
<0.05
4
Q
What p-value is used if Genome-Wide Association Study is used?
A
5x10(^-8)
5
Q
A high p-value means you (accept/reject) null hypothesis
A
Accept
6
Q
T/F: A p-value measures the strength of association
A
FALSE
7
Q
T/F: Odds ratio measures strength of association
A
TRUE
8
Q
What is the Odds Ratio?
A
Odds of phenotype in individual with the genotype/odds of phenotype in individual without genotype
9
Q
What does OR =1 mean?
A
No association
10
Q
What does OR > 1 mean?
A
Allele is associated with Increased Risk
11
Q
What does OR<1 mean?
A
Allele is associated with decreased risk (protective allele)
12
Q
95% CI >1:
A
Statistically significant increase in risk
13
Q
95% CI including 1
A
No statistically significnat difference
14
Q
95% CI <1
A
Statistically significant decrease in risk (protective effect)
15
Q
What is LEM caused by?
A
GOF in Nav1.7
16
Q
What does LOF in Nav1.7 cause?
A
Insensitivity to pain
17
Q
What alleles can be treated with CBZ?
A
V400M
S241T
NOT F1499
18
Q
What is MEA?
A
A way to measure action potentials without dilating cell
19
Q
What is iPSC?
A
Can make stem cells identical to host to test drugs on without exposing patient to them
20
Q
What is the most common CYP?
A
CYP3A
21
Q
What are the CYP2D6 variants?
A
- 1: Normal
- 9, *10: Reduced
- 3-*6: No function
22
Q
What is the clinical significance of CYP2D6?
A
Codeine Hydrocodone Nortriptyline Fluoxetine Metoprolol Carvedilol Tramadol
23
Q
What are the CYP2C9 variants?
A
- 1: WT
* 2, *3: Low function
24
Q
What drugs are affected by CYP2C9
A
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
