identify genetic differences in people that affect drug response
develope genetic tests that predict an individual's response to a drug
tailor treatments to the individual
Pharmacogenetics
evaluation of how an individual's genetic make-up corresponds to their response to a medication
Pharmacogenomics
combines pharmacogenetics with genomic studies
uses large groups of patients to evaluate how candidate drugs interact with a range of genes and their protein products
A combination of alleles (for different genes) that are located closely together on the same chromosome and that tend to be inherited together
Haplotype
_____ are those expressed in DNA sequences that become the mRNA
Exons
A___ is found in the cell nucleus and consists of one very long DNA molecule and associated proteins
Chromosome
The exchange of one nucleotide for another. Considered the most common genetic variation in human DNA, occurring approximately once in every 300 base pairs.
Single nucleotide polymorphism
A double-stranded, helical nucleic acid molecule capable of replicating and determining the inherited structure of a cell's proteins
DNA
Genetic variations that occur at a frequency of at least 1% in the human population
polymorphisms
_____ are those intervening sequences of DNA that are removed in the process of making a mature mRNA.
introns
The genetic makeup of an organism
Genotype
a section of DNA or RNA that is 3 nucleotide pairs in length that codes for a single amino acid.
codon
physiological trains of an organism
phenotype
alternate version of a gene
allele
a rare (occurs in <1% of the population) change in the DNA of a gene ultimately creating genetic diversity.
mutation
A unit of heredity in a living organism
Gene
Percentage of our DNA that is the same as a monkey
93%
Percentage of our DNA that is the same in humans
99.5%
If all DNA in the body is streched out it is
6 ft long
Why do we care so much about proteins?
essential components of living cells
necessary for building and repair of body tissues
drug transporters
metabolic enzymes
receptors
Alternative versions of genes are
alleles
DNA at a specific location can vary in nucleotide sequence meaning it varies in
genotype
Percentage of DNA that is "junk DNA" or introns which regulate transcription
95%
Percentage of DNA that is exons or expressed traits
5%
Single nucleotide polymorphism (SNPs)
most abundant type of genetic variation
~1 SNP in every 300-500 bp
~10,000,000 SNPs in the human genome
Number of SNPs in the coding DNA (exons)
500,000
Mechanisms by which SNPs may affect genes even if located in introns
DNA stability
Folding/unfolding
gene spacing
Other types of polymorphisms
more than one nucleotide change
entire gene insertion or deletion
extra copies of a gene
Types of Genetic variations
Insertion
deletion
base pair change
how are SNPs relevent to a pharmacist?
SNP change the amount/function of a protein that contributes to drug response
may alter pt sensitivity to a drug
may cause adverse reactions to a drug
Polymorphism with no effect
no change in translated amino acid
codon encodes for the same amino acid
corruption of the genetic code
no functional significance of amino acid substitution
Minimal effect polymorphism
amino acid substitution results in minimal differences in protein structure or function
significant effect of polymorphism
amino acid substitution results in significantly altered protein structure or function
altered substrate affinity of CYP450 enzyme
Systems for pharmacogenomic nomenclature
allele numeric/alphabetic
SNP nomenclature
allele "star"nomenclature
genotype nomenclature
haplotype nomenclature
What is an allele?
variant and wild type forms of a gene at a particular location on a chormosome
each nucleotide base in the gene can be considered an allele
An example of a SNP is the VKORC1 1173 C>T. Based on the pharmacogenomic nomenclature of this SNP, what is the gene of interest?
C. VKORC1
What is a genotype?
2 alleles that any individual has
If you see *#/*# then
we are looking deeper to find if there is a difference in the genotype
What is a haplotype?
a set of alleles at multiple locations that coexist on the same chromosome
Synonymous SNP
results in the same amino acid being transcribed
Non-synonymous SNPs
result in amino acid substitution
A polymorphism has been found for a drug-metabolizing enzyme. A nucleotide change occurs, yet the resultant amino acid is unchanged. What type of SNP is this?
B. Synonymous
A polymorphism has been found for a drug metabolizing enzyme. A nucleotide change occurs, resulting in a change in the amino acid. What type of SNP is this?
C. Non-synonymous
When patients have haplotype 7 & 2 they have a reduction in response to statins by
25%
What is the ultimate goal of pharmacogenetics
use genetic info to choose a drug, dose and treatment duration best for the patient
