Pharmacogenetics Flashcards
What is pharmacogenetics?
- genetically controlled variations in drug response
- genetic factors that alter an individual’s drug response to a drug
- genetic polymorphisms
- less common genetic variants
State the importance in recognizing genetic differences in individuals:
- Genetic differences can cause significant differences in the dose of a drug required to achieve the desired effect.
- Genetic differences in drug metabolism can significantly alter drug clearance and pharmacokinetics.
- Genetic differences can alter susceptibility to toxic effects of drugs and other chemicals.
- Genetic differences can cause or exacerbate adverse drug reactions, some of which used to be called “idiosyncratic”.
- These patients do not become apparent until they are exposed to a particular chemicalor drug.
Genetic locus:
chromosomal location at which two alleles are possible
Genotype:
- an individual’s **composition at the gene level **
- i.e. the specific genes they have
Phenotype:
an individual’s expression of their genotype
Genetic polymorphism:
- Mendelian trait that exists in the population in at least two phenotypes neither of which is rare
- i.e. at least one variant that represents greater than 1% of total pool
Allele:
- an alternative form of a gene
- one of the different forms of a gene that can exist at a single locus
Single nucleotide polymorphism (SNP):
- a change in one single base pair in the DNA sequence that differs from the “wild type” or predominant sequence
- may or may not result in an altered phenotype
- 99% do not change the phenotype
- most common polymorphism
How do we categorize individuals based off of SNPs?
- Haplotypes
- Halotypes
Haplotype:
- refers to closely linked genetic markers on a chromosome that tend to be inherited together
- often within a gene or closely linked genes
Halotypes:
- refers to a cluster of SNPs that occur together in an individual (andare of interest to a phenotype)
- useful for categorizing individuals to understand how clusters of SNPs can contribute to phenotype
-
multiple SNPs may be:
- in a single gene (similar to a haplotype)
- multifactorial, multiple genes not necessarily inherited as a unit
Types of inheritance:
- Autosomal co-dominance: each allele contributes to phenotype
- Autosomal recessive: wild-type allele has predominant effect; it takes two recessive alleles to see the effect
- Autosomal dominant: a single allele predominates over the presence of other possible alleles
- X-linked inheritance: genes inherited on X chromosome; all males will express these traits (males are hemizygous)
Hardy Weinberg equilibrium:
- In populations with random mating and no selection pressure, the incidence of the various genotypes can be determined mathematically
- This description is the Hardy Weinberg formula:
1 = (p+q)2=p2 +2pq +q2
where:
- p = proportion of wild type alleles
- 2pq = frequency of heterozygote
- q = proportion of variant alleles
- p2 = frequency of homozygous WT
- q2 = frequency of homozygous variant
- If frequencies of observed phenotypes fit the equation, a variant is said to be
consistent with Mendelian inheritance
homozygous:
have 2 identical alleles
- e.g. AA or aa
Pharmacogenetics versus pharmacogenomics:
- Pharmacogenetics: variation at selected loci
- Pharmacogenomics: whole genome variation
What are some potential genetic polymorphic impacts on drug efficacy & toxicity:
- Polymorphisms which could impact pharmacokinetics:
- Transporters (uptake, distribution)
- Plasma protein binding
- Metabolism
- Excretion
- Polymorphisms which could impact pharmacodynamics:
- Receptors
- Ion channels
- Enzymes
- Signaling events
NAT-2 polymorphism:
Initial observations
- Increased neurologic side effects in some patients were correlated with increased plasma concentrations of isoniazid
- Plasma half-life phenotype in population identified two groups, and implicated a difference in elimination/metabolism
- Subsequently established that genetic differences in NAT-2 explain “fast” versus “slow” acetylators
- autosomal recessive trait

____________ responsible for metabolism of the anti-tuberculosis drug isoniazid
- N-acetyltransferase-2 (NAT-2)
Other drugs influenced by N-acetylation phenotype:
- hydralazine
- nitrazepam
- procainamide
- phenelzine
- dapsone
- clonazepam
- sulfonamides
- others
Slow acetylator phenotype has been associated with:
- increased incidence of neuropathy due to isoniazid
- arylamine-associated bladder cancer
- hypersensitivity to sulfonamides
- higher incidence of lupus erythematosus with long-term hydralazine therapy
CYP2D6 Polymorphism:
- First identified from those that suffered severe hypotension following administration of the anti-hypertensive debrisoquine
- Severe hypotension associated with increased debrisoquine concentrations, and decreased metabolism of debrisoquine
- Subsequently linked to “poor metabolizer” variants of CYP2D6
Poor metabolizer variants of CYP2D6:
- CYP2D6 variant alleles
- Autosomal gene
- >75 variants identified
- Frequency of poor metabolizer allele and phenotype:
- Mutant allele frequency about 30%
-
Poor metabolizer phenotype frequency:
- 2–10% of population
- (ethnic variation)
Ultrafast CYP2D6 metabolizers
- CYP2D6 gene duplication (up to 13 copies) of the normal allele
- Incidence among different ethnic groups (varies from 1–30%)
- Clinical trials of nortriptyline clearance in patients show much more rapid drug clearance in those with multiple copies of functional CYP2D6
Why are CYP2D6 polymorphisms important?
- CYP2D6 metabolizes about 25% of metabolized prescription drugs, including:
- β-blockers
- antiarrhythmics
- antidepressants
- neuroleptics
- some opiates
- others