The first pharmacogenomics studies were on variable __________ effects on neuromuscular blockade and __________ neurotoxicity
succinylcholine
isoniazid
the science that examines the inherited variations in genes that determine drug responses is
pharmacogenomics
variability with regards to pharmacokinetics parameters is
pharmacogenetics
Pharmacogenomic includes individualizing the dose based on variability in _____________ and _________
molecular targets
other PD parameters
Isoniazid is activated by the
multifunctional catalase-peroxidase KatG
Isoniazid is inactivated by __________ by _____________
acetylation
hepatic arylamine N-acetyltransferase
Vitamin K epoxide reductase (complex subunit 1) is coded for by the
VKORC1 gene
Severe neurological effects observed in ___________ of isoniazid
slow acetylators
debrisoquine elimination is due to variability in __________ or _________
debrisoquine hydroxylase
CYP2D6
DNA for any two humans varies by _________________
~ 1 base/1000 bases
Types of Genetic Variants include
SNPs
indels (insertions & deletions)
copy number variations
A ______________ substitution that arises in >1% of the population is called a single nucleotide polymorphism (SNP).
single base-pair
66% of the SNPs are _____________ substitutions
C -> T
Base change -> change in protein amino acid
Nonsynonymous SNP
a silent polymorphism that where the substitution does not change the final amino acid in the protein – however can still get alteration in the functional protein
Synonymous SNP
the nucleotide substitution results in a stop codon being introduced
Premature Stop Codon SNP
Protein chain synthesis is terminated and a shortened protein is produced
Premature Stop Codon SNP
If at least two genes or SNPs are located near each other, then they will tend to stay together through recombination
Linkage Disequilibrium
one can use the presence of one SNP to infer the presence of other SNPs if they all show strong linkage disequilibrium. This called a _____________
tagging SNP
The S-form of warfarin is metabolized by __________
CYP2C9
VKORC1 gene codes for
Vitamin K epoxide reductase (complex subunit 1)
__________ are responsible for PK genetic variability for warfarin
CYP2C9 polymorphisms
____________ are responsible for PD genetic variability for warfarin
VKORC1 polymorphisms
How many alleles of CYP2C9 are known to cause reductions in enzyme activity for warfarin
2
how many SNP haplotypes of the VKORC1 gene have been shown to be associated with modified functional activity of the enzyme complex
2
VKORC1 hapotypes contain 30 SNPs in the __________ region of the gene
non-coding
In regards to warfarin dosing, 5 of the SNPs of the VKORC1 were found to exhibit strong _____________ forming two haplotypes
linkage disequilibrium
Using an algorithm including pharmacogenetic
information for ______ and _________ is more accurate in targeting treatment to a defined INR for warfarin dosing
CYP2C9
VKORC1
A change in bases pairs that results in a change in amino acid sequence is
nonsynonymous SNP
A change in base pairs that does not alter the final amino acid sequence is
synonymous SNP
A change in base pairs that result in -->TAG is
premature stop
An example of an allele with a premature stop codon is
CYP2C19*3
In order for SNPs to be tagging SNPs, they must show ______
linkage disequilibrium
What is responsible for PD variability in warfarin dosing?
vitamin k epoxide reductase complex subunit 1 polymorphisms