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MOD 1&2
Pharmacogenomics
62
Biochemistry
Graduate
01/04/2017

Additional Biochemistry Flashcards

 


 

Cards

Term
PHARMACOKINETICS
Definition

What the body does to drug [conc. v time]

[image]

Term
PHARMACODYNAMICS
Definition

WHAT THE DRUG DOES TO THE BODY [conc v effect]

 

study of relationship between rx conc. at site of action & ther & adverse effx

Term
PK/PD
Definition
effect v time
Term
Therapeutic Goal
Definition
Treat pt w/ right drug at right dose at right time to improve/cure disease
Term
Therapeutic window
Definition

difference in min effective dose and minimum toxic dose

 

[image]

Term
Target site conc v Plasma conc
Definition

Determining actual target site conc = difficult

Drug targets not in blood/plasma(found in tissue/organs)

Plasma conc cn be used to optimize dose regimen

 

Plasma concentrations correlate well w/ those in tissue

Term

Therapeutic drug monitoring

[TDM]

Definition

Use assays to determine drug plasma conc and interpret/apply resulting conc to retrospectively develop safe and effective regimen

 

[for narrow ther index rx's]

Term
TDM (therapeutic drug monitoring order)
Definition

1. Dx , Rx selection

 

2. Start ther. w/ standard dose

 

3.Rx levels monitored

 

4. PK model applied to obtain individ. dosing reg.

 

5. Individ. dosing reg

 

Term
Pharmacogenetics (PGx)
Definition
investigations providing info about person's gene meakup addressing questions about the choice of drug and drug doses for pt
Term
Factors responsible for PK Variability
Definition

Demographics 

Drug-Drug intrxn

Genes

Environment

Lifestyle habits

Term
Drugs w/ PGx info
Definition

Abacavir

Plavix

Strattera

CISplatin

Coumadin

Codeine

Term
PGx info on labels
Definition

Actionable = 44%

Required = 24%

Recommended = 4%

Informative = 28%

Term

Pharmacogenetics vs Pharmacogenomics

influencing response to drugs

Definition

Pharmacogenetics = genetic dif at single variation/locus(gene)

 

 

Pharmacogenomics = genetic dif in multiole genes(genome wide) 

Term
Values of Pharmacogenomics
Definition

Optimizes rx therapy

 

using tech for personalized rx

 

optimize rx development

Term

Metabolism and receptor types 

 

WT-WT

 

WT-V

 

V-V

Definition

WT-WT = normal profile [min toxicity, great ther effect]

 

WT-V = inc drug exposure 2x [toxic, min ther effect]

 

V-V = inc drug exposure 4x [too toxic,no ther effect]

Term
Pharmacogenomics -Guided therapy EXAMPLES
Definition

1. Dose rec: Warfarin, atomoxetine

2. Indication: trastuzumab, imatinib, dasatinib

3. Increased serious ADR or Tx failure risk: carbamazepine, valproic acid

4. Contraindictaion: abacavir, fluorouracil

5. General warning/precautionary statements/ need for dose reductions based on rx metabolizing phenotype : atomoxetine, mercaptopurine, modafinil, clopidogrel, codeine

6. others with explicit/implicit evidence that no dose adjustment required by phenotype

Term

WARFARIN LABEL

 

CYP2C9 & VKORC1

Definition

KNOWLEDGE OF GENOTYPE CAN INFORM INITIAL DOSE SELECTION

 

-iNDIVID. DOSE PER PT

 

- INR OBTAINED DAILY TILL STABLE THER. RANGE ACHEIVED (THEN EVERY 1-4 WEEKS)

Term

Varient CYP2C9 in warfarin use results in...

 

 

SNP to VKORC1 result in....

Definition

decreased metabolism of s-warfarin (7-HYDROXYLATION)

 

 

 

 

variable warfarin dose reqs.

Term
Plavix LABEL
Definition
-CYP2C19 = poor metabolizers have smaller effect when taking plavix [have higher CV events]
Term
genome
Definition
entire genetic make up of an organism
Term
DNA made of
Definition

SUGAR-PHOSPHATE backbone

 

4 nucleotides (adenine, thymine, cytosine, guanine)

 

Term
Human Genome project
Definition

1990-2003

 

Goals= 

-identify all enes in human DNA

-store info in database

-determine sequences of 3 billion BPs

-address issues

Term

average gene has ______ base pairs (varies greatly)

 

 

Human chromosomes have ______ BPs

 

Less than ____ of genome codes for protien 

Definition

average gene has 3,000 base pairs (varies greatly)

 

 

Human chromosomes have 150,000 BPS

 

Less than 2%of genome codes for protien 

Term
Central Dogma of Molecular bio
Definition

DNA to DNA [replication]

 

DNA   to   RNA  [transcription]

 

RNA   to   protein [Translation]

 

*****HIV>>>>RNA bac to DNA (retrovirus)

Term

EXONS ARE......

 

INTRONS ARE......

 

UTR

Definition

EXONS ARE protein coding regions that are SPLICED together

 

 

 

INTRONS ARE noncoding/ SPLICED out

 

UTR = untranslated regions

Term

START CODON= 

 

 

STOP CODONS = 

 

CODON = 

Definition

START CODON(1st nucleotide) = AUG

 

 

 

STOP CODONS(2nd nucleotide) = UAA,UAG, UGA

 

CODON = 3 NUCLEOTIDES

Term
GENOME vs EXOME vs REGULOME
Definition

GENOME = entire genetic makeup [genes,exonx,introns]

 

 

EXOME = only the exons of our genes [protein coding parts]

 

REGULOME = DNA elements that modulate gene expression

 

Term
REGULOME
Definition
Term
SNP
Definition

-single nucleotide polymorphism

-change in single BP

-Occurs approximately every 300 BPs

 

ex: GATCT

     GATTT

Term

Insertion/Deletion [IN/DELS]

 

Definition

-insertion or deletion of one or more BPs

 

 

ex: GATCTGA

       GATCCTGA

Term
VNTR
Definition

-variable number of tandem repeats

-consecutive BP groups that are differentially repetitive

 

-Microsatelite, minisatellites

 

ex: AG(TA)n

     

     AG(TA)5

vs  AG(TA)7

Term
CNV
Definition

Copy number Variation

-whole gene copies or varirations

 

Term
Poolymorphisms cause....
Definition

Nonsense SNP = premature stop codon[nonfunctional protein]

 

Nonsynonymous = Change in codon causing dif amino acid [change in protein]

 

Intronic or UTR = changes in mRNA level or stability

 

Promotor or enhancer region = chnages in gene expression/ how much RNA/protein is made

Term

 SNP NOMENCLATURE 

 

CYPC2C19 681 G>A

 
Definition




GENE  POSITION   ALLELE1>ALLELE2


-SNP can be given rs # [reference SNP#]

Term

ALLELE NOMENCLATURE 

 

CYPC2C19 681 G


Definition

GENE  POSITION   ALLELE


[can have * CYP2C19*1]

Term
HARDY WEINBERG EQUILIBRIUM
Definition

p = Freq (A)

q = Freq (a)

p + q = 1

 

 

p2 + 2pq + q2 = 1

Term
Lab error with polymorphisms is mostly associated with
Definition
Something out of Hardy weinberg equilibrium
Term
Recombination can....
Definition

NOT occur at any point in the HUMAN GENOME

 

[recombination occurs between blocks]

Term

Block sizes 

 

European =

 

African = 

Definition

European = 44 kilobases

 

African = 22 kilobases

Term
Linkage disequilibrium
Definition

tendancy for pairs of alleles at nearby loci

to be associated with each other more often than

 

expected by chance if the loci were segregating indipendently in the pop

Term

Measure of LD [linkage disequilibrium]

 

values greater than or equal to 0.70-0.80 is considered in "high" LD

Definition

D'

from 1 (complete LD;no ancestral combo)

to 0 (no LD;independent assortment)

 

r2

from 1 (perfect LD,no ancestral recombo, and the 2 SNPs have the same allele frequency)

to 0 (no LD;independent)

 

Term

Factors that influence LD

[LD provides basis for most association disease strategies]

Definition

REcombination [time,distance]

 

Mutation

 

Admixture,pop stratification/structure

 

pop growth, nat selec., gene drift

 

 

Term

Haplotype

 

 

Diplotype

Definition

Haplotype = combo of alleles or SNPs along chromosome that tend to be inherited together.

 

 

Diplotype= 2 haps inherited for certain gene, or combo of alleles or SNPs

Term

LD and Haplotypes 

 

 

Theory vs Reality

Definition

Theory = lots of SNPS

 

 

Reality = Fewer haplotypes are actually observed

Term
Pharmacogenomic testing challenges
Definition

-access

 

-feasibility

 

-cost

 

-level of evidence

Term
Issues w/ personal genome testing
Definition

-ancestral pop SNPs were discovered in

 

-# of SNPs tested

 

-average population risk used

 

-Algorithm used to predict your risk based on genetic information

 

-Single SNP vs Haplotype based analyses

Term
Knowledge gap w/ genetics/testing
Definition

-lack of clinical utility for pharmacogenetic testing

 

-health info tools need pharmacogenetic info at point of care for clinical decision support

 

-healthcare professionals need edu

(field growing fast w/ new discoveries = PRACTICE GAP)

Term
***DATABASE PROCESS***
Definition

Lit review>>PUBMED>>

 

1.SNP info

[NCBI SNP,HapMap]

2.Gene info

[NCBI gene,UCSC genome browser,PharmGKB]

3.Disease Info

[NCBI OMIM, Huge Navigator]

Term
Limit results in databases with....
Definition

Boolean operators =

 

AND

NOT

OR 

 

 or COMBINATION of these

Term
1000 Genomes project
Definition

Goal was to find most genetic variant that have frewuencies of at least 1% in the populations studied

 

-tool used for

1. look at allele frequencies (BEST PLACE***)

2.pop. [ancestry groups]

Term
Best browser place for gene expression....
Definition
UCSC
Term
WHere to look for biological pathways....
Definition

-PharmGKB 

 

-KEGG

Term
Other SNP references
Definition

Haploreg

 

 

SNPs 3d

Term
Geome wide association studies
Definition

NCBI dbGaP

 

 

NHGRI

Term

GENE & DISEASE

 

SNP

 

PATHWAY INFO

 

GENOME WIDE ASSOCIATION STUDIES

Definition

GENE & DISEASE [NCBI Gene,OMIM, HuGE, UCSC]

 

SNP [NCBI SNP,1000 Genomes, Haploreg & SNPs 3D]

 

PATHWAY INFO [PharmGKB,KEGG]

 

GENOME WIDE ASSOCIATION STUDIES [NCBI dbGaP, NHGRI catalog of Genome Wide Association Studies]

Term
info on prior studies*
Definition
1st pubmed
Term
info on SNPs
Definition

NCBI SNP

 

1000 Genomes (allele freq)

Term
Gen info*
Definition

NCBI Genome

 

UCSC Genome Browser (gene expression)

 

Term
Disease info**
Definition

HuGE Navigator

 

OMIM

Term
Pathway
Definition

PharmGKB

 

KEGG

Term
Pharmacogenomic INFO***
Definition
PHARMGKB
Term
INFO ON GENETIC ASSOCIATIONS**
Definition

UCSC genome browser

 

HuGE Navigator 

 

dbGaP

 

GWAS catalog

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