Flashcards in Exam 1 Deck (164):
What is the null hypothesis?
There is no association between alleles and phenotype
Does a large or small Chi Square support the null hypothesis?
What p-value is used for an association if only a specific SNP is being tested?
What p-value is used if Genome-Wide Association Study is used?
A high p-value means you (accept/reject) null hypothesis
T/F: A p-value measures the strength of association
T/F: Odds ratio measures strength of association
What is the Odds Ratio?
Odds of phenotype in individual with the genotype/odds of phenotype in individual without genotype
What does OR =1 mean?
What does OR > 1 mean?
Allele is associated with Increased Risk
What does OR<1 mean?
Allele is associated with decreased risk (protective allele)
95% CI >1:
Statistically significant increase in risk
95% CI including 1
No statistically significnat difference
95% CI <1
Statistically significant decrease in risk (protective effect)
What is LEM caused by?
GOF in Nav1.7
What does LOF in Nav1.7 cause?
Insensitivity to pain
What alleles can be treated with CBZ?
What is MEA?
A way to measure action potentials without dilating cell
What is iPSC?
Can make stem cells identical to host to test drugs on without exposing patient to them
What is the most common CYP?
What are the CYP2D6 variants?
*9, *10: Reduced
*3-*6: No function
What is the clinical significance of CYP2D6?
What are the CYP2C9 variants?
*2, *3: Low function
What drugs are affected by CYP2C9
A LOT--including warfarin, phenytoin, tolbutamide, glipizide
T/F: All drugs are affected the same by CYP2C9
FALSE: Do not assume clinical significance unless studies have shown it
What is the clinical relevance of CYP2C19?
Clopidogrel (increases activity because PRODRUG)
Antidepressants (citalopram, escitalopram, sertraline)
What are the variants of CYP3A4
What are the variants of CYP3A5
(*3 is NORMAL)
What is the clinical significance of CYP3A4/5
Tacrolimus, cyclosporine, simvastatin
Are CYPs Phase I or Phase II?
Are UGTs Phase I or Phase II?
What are the UGT families?
What do UGTs do?
Conjugate enzymes -- transfer glucuronic acid to substrate
What is the UGT1A1 variant?
*28--decreased function (an extra TA in TATA box)
UGT1A9's most studied variant?
UGT1A9 clinical significance?
(all increased exposure)
What does TPMT variant increase the concentration of?
What does increased TGN lead to?
What drugs are affected by TMPT?
In homozygous variant for TMPT, decrease dose of drugs by how much?
10-fold! and only give 3 times a week
What drugs with NAT?
Variants of NAT?
Not any 4s: SLOW
Containing a 4: Rapid
Where is OATP1B1 found?
What does SLCO1B1 code for?
What does decreased OATP1B1 do?
Increase systemic circulation
What are variants of SLCO1B1?
*15: real low
Clinical relevance of SLCO1B1?
Also reduces efficacy
What does decreased PGP efficacy do?
Increase bioavailability (prevents re-efflux into intestinal lumen)
Increase hepatocyte exposure (prevents excretion to bile)
What is BCRP?
Efflux transporter in gut and liver
Clinical significance of BCRP?
Increased exposure to sulfasalazine, rosuvastatin, topotecan, gefitnib (NOT irinotecan or pravastatin)
What does OCT1 do?
Hepatic uptake of drugs into the liver
What drugs are affected by OCT1?
Metformin - reduces efficacy but increases plasma concentrations
What disease does adducin cause?
What drug class can be effective in treating?
What disease do Prothrombin and Factor V cause?
Associated with what drug class?
DVT and thrombosis
What disease does Apolipoprotein E contribute to?
Alzheimer's and atherosclerosis
What drugs are used to treat atherosclerosis with APOE polymorphism?
What drug is used to treat Alzheimer's with APOE polymorophism?
What disease is caused by Cholesterol ester transfer protein?
What drug can slow progression?
G6PD deficiency can cause what ADR?
HLA-B*1502 mutation causes what ADR? In what population?
Fatal skin reactions in Asians
HLA-B*5701 mutation causes what ADR? What drug?
Immunological ADRs--rash, fever, GI/respiratory distress
Bradykinin B2 receptor causes what ADR? What drug?
DHP receptor Ca channel mutations cause what ADR? What drug?
Mutated cardiac ion channels cause what ADR?
QT Prolongation and TdP
What mutation in what receptor is associated with more severe asthma?
Gly16 allele in Beta2 receptors (ADRB2)
What are microRNAs?
Noncoding genes, play important role in regulating protein-coding gene expression
What direction is DNA read?
5' --> 3'
What project allowed development of a reference genome?
Human Genome Project
What is the position of each nucleotide within the reference genome called?
Which is unwound--chromsome or chromatin?
What is a karyotype?
The complete picture of a genome in a cell
T/F: In all parts of the central dogma (DNA, RNA, protein), things can replicate themselves
T/F: DNA can be made from RNA
T/F: RNA can be made from protein
Where does mRNA maturation process occur?
In the nucleus
What happens during mRNA translation?
Poly-A tail added, introns removed
T/F: There is a 5'UTR and a 3'UTR in matured mRNA
Translation starts with what codon?
What are the 3 stop codons?
UAG, UAA, UGA
Does the ORF include the stop codon?
No--stops at codon before
How many codon?
How many amino acids?
What is a polymorphism?
A sequene variation at the same position of HOMOLOGOUS CHROMOSOMES
Are there polymorphisms in the genome of a signle germ cell?
No it is haploid, so doesn't have homologous chromosomes
What is a hemizygote?
one allele is present, the other is missing (type of heterozygousness)
What is Mendel's Law?
Parents pass randomly selected allele to offspring
What is the UGT1A1 polymorphism?
Number of TATA boxes in promoter
6 or 7 are common
7 --> reduced gene expression
What's the difference btween
c.1297 G>A and p.Val433Met
c: in coding region, count nucleotides
p: protein position, count amino acids
CYP2C19*2D - Missense, nonsense, splicing defect, indel?
CYP2C19*3A - Missense, nonsense, splicing defect, indel?
CYP2C19*17 - Missense, nonsense, splicing defect, indel?
Whay CYP2C19 are intermediate metabolizers?
*1/*2, *1/*3, *2/*17
What CYP2C19 are extensive metabolizers?
What is MAF?
Minor allele frequency--percent of less common allele
What is a haplotype?
A group of genes inherited together from single parent
Inheritance of a cluster of SNPs (together)
What is linkage disequilibrium?
Non-random association of genes at different loci on the same chromosome (things closer together are inherited together more often)
If two SNPs are really close, LD = ?
If two SNPs are rally far, LD = ?
What is R2?
a measure of correlation b/w two variables
What R2 is considered strong LD
What is a tagSNP?
A SNP representative of other SNps due to strong LD with them
What is the Human genome project's goal?
Complete mapping/understanding of all genes of human beings
-Map a reference genome
What is the HapMap Project?
continued study from HGP--studies in DNA variation
What are the benefits from HPG?
a REFERENCE SEQUENCE! - powerful tool for research
What is the HapMap Project goal?
to ID sequence variations among
(ID SNPs/tagSNPs in haplotypes)
Which population has most polymorphisms found in other populations accoring to HapMap?
What has replaced HapMap?
1000 Genome project
What's the goal of the 1000 Genome Project?
Identify variants with frequencies of at least 1%
What provides a genome browser to view 1000 Genomes Project on current reference genome?
What is 1st pharmacogenetic resource?
What are CPIC Guidelines?
Clinical Pharmacogenetics Implementation Consortium (tells you how genetic variations should influence treatment)
Which CYP2C9 variants are more important for African American?
Peripheral blood as DNA sample - special patients to not use in?
Patients with chemo
Bone marrow transplant patients
What type of tube for blood cell DNA collecting?
What are limitations of cheek swabbing for DNA?
-Less DNA yield
When do you take tissue samples for DNA?
(use dry ice for transportation of fresh biopsy)
What temperature can DNA be stored at short term?
What temperature can DNA be stored at long term?
What process is used for DNA amplification?
How does PCR work?
Amplifies a specific region from the genome to make billions of copies so it is more detectable
What are the steps for PCR?
Denaturation (temperature increased)
Annealing (temperature decreased)
Extension (polymerase extends)
What is the total number of DNA at the end of PCR?
N = cycles
Does PCR amplify both chromosomes?
yep--both homologous chromosomes
Ned more tech to identify specific alleles
DNA Chip: known or unknown SNPs?
DNA Chip: High throughput or low throughput?
DNA Chip: Cost?
Medium cost, low per SNP
What is Amplichip CYP450 Array?
Chip-based Pgx teting platform, FDA-approved by Roche
Used for CYP2D6 and CYP2C19
What are the 2 sequecning methods?
next generation sequencing
Sanger: high or low throughput?
Sanger: Targeted or not?
Next generation sequencing: High or low throughput?
Next generation sequncing: target or not?
Sanger sequencing is based on selective incorporation of ______ by DNA polymerase
What type of DNA sequencing method relies on PCR amplification?
How does NGS sequence?
By synthesis--builds the DNA and lights up depending on what's added
What depth of coverage is recommended for human genome mutation detection? (How many times should each SNP be detected to count)
10 to 30x
T/F: DNA chips are used for detecting somatic mutations
False: usually not used due to inaccurate readings for imbalanced mutant/wildtype copies
What is karyotyping used to detect?
chromosomal rearrangement (Philadelphia chromosomes)
What act limited data sharing from genetic issues?
GINA - Genetic Information Non-Discrimination Act
How can CYP2D6 be ultrarapid?
CNV - more copies of normal functioning gene
Which alleles for CYp2D6 are non-functional, which are reduced function?
Reduced function: 9-10
Which drug is a prodrug of CYP2D6 ?
CYP2C9 has what reduced function alleles?
Which CYP2C9 genotypes are intermediate? which are poor metabolizers?
Int: *1/*2, *1/3
Poor: *2/2, *2/3, *3/3
*2/*17 CYP2C19 allele is what type of metabolizer?
CYP2C19 normal metabolizer?
Which CYP3A5 alleles have LOF?
3, 7, 6
What raises of CYP3A5 present?
50% of African americansa
1/3 of hispanic and Asian
how do you change tacrolimus if someone has CYP3A5?
Increase starting dose 1.5-2x
UGT1A1 has what variant?
*28 - 7 copies of TA in TATA box
UGT1A9 has what variant?
*3 - reduced function
Substrates of TPMT?
Variants of TPMT?
*1/N --- N means reduce dose
N/N means reduce dose A LOT
What is NAT reference allele?
How is NAT grouped?
Slow - has a *4
Rapid - does not have a *4
What are intermediate SLC01B1 phenotypes?
What genes encode PGP?
PGP affects what drug?
Reduced PGP function affects bioavailability how?
Increases--less efflux back into GI
Reduced PGP function affects hepatotoxicity how?
Increases -- less excretion into bile (so higher concentrations in liver)
What gene encodes BCRP?