Pharmacogenetics Tutorial Flashcards
Describe distribution of polygenetic control
- Several genes act together to give rise to a continuous or unimodal (gaussian) distribution of the measured variable. It is not possible to recognise or discern the influences of single genes
- Large differences between individuals at the extremes
Give an example in drug metabolism of polygenetic control
Salicylate conjugation with glycine or glucuronic acid
Describe the distribution seen in monogenetic control
- Owing to the action of a single gene that has a large overriding effect. This gives rise to a discontinuous or multimodal distribution of the measured variable.
- An observed bimodality, for example, would strongly suggest that the population consisted of two types of individual with regard to the property measured. These would be two phenotypes.
List the phenotypes seen in drug metabolism
- Enhances/ extensive (low plasma conc of the drug, usually heterozygote or homozygote dominant)
- Intermediate metaboliser
- Poor/ slow metaboliser (slow drug metaboliser, high plasma conc. Homozygote recessive)
How can pharmacogenetics be investigated?
- Population studies (look at distributions - multimodal or monomodal)
- Family studies (look at the dominance model)
- Molecular biology (gel electrophoresis)
What is pharmacokinetics used for?
- Used to predict the reaction of patients to drugs, and determine whether the patient will experience severe toxicity
- The study of genetically determined individual differences in the therapeutic response to drugs and susceptibility to adverse effects (restricted to one or few genes of interest and mendelian segregation)
Define pharmacogenomics
- Use of genome based techniques in drug development
- Not restricted to one or few genes
- Use of high-throughput technologies
List the types of determinism of a trait
- Monogenic (variation of a single gene)
- Polygenic (two or more genes)
- Polymorphic (frequently occurring monogenic variants at a frequency of more than 1%)
How is the genotype and phenotype identified?
- Genotype by PCR
- Phenotype by determination of metabolic rate by measuring pharmacokinetic parameters after drug administration
How can family studies be used in pharmacogenetics?
- If more than 1 phenotype is present in a family this means there are at least 2 alleles
- Typically seen at the protein synthesis level
- Used to get the dominance model, as heterozygous phenotypes are dependent on the dominant trait (eg. if parents have a different phenotype to a child they must be heterozygous, therefore their phenotype must be dominant)
How is Hardy-Weinburg used in pharmacogenetics?
- Both allele and genotype frequences in a population remain constant unless specific disturbing influences are introduced, given that everyone is free to breed with who they want
(p+q)^2 = (p^2 + q^2 + 2pq = 1
- Therefore, once the recessive allele has been determined (eg. slow acetylation of sulphadimidine) q can be found by square rooting the probability of a person having the recessive trait
- This value is then substituted into the equation to find the dominant trait, as p + q = 1
- This can then be used to find p^2 (probability of dominant trait) and pq (probability of recessive trait)
How can N-acetylation polymorphism be measured?
Testing urine for concentration of the product of N-acetylation using a dye that turns the product present in urine blue
What is the antimode?
- The local minimum
- In N-acetylation 0
- However, usually there is some overlap of the phenotypes
Describe gel electrophoresis in n-acetylation
- Wild type fast acetylator phenotype
- Homozygous M1/M1 polymorphism (slow acetylator phenotype)
- Heterozygous M1/wild-type
- M1 polymorphism differs by substituation of T to G. Therefore, this introduces a new restriction site.
- Therefore, people with a mutation at the restriction site (slow metabolisers) will form more fragments and therefore DNA will not move as far. Slow has 2 fragments and moves further, fast 1 and moves less far. Homozygous has 3 bands.
Compare genotype and phenotype
- Genotype is the gene sequence encoding for the given characteristics
- Phenotype is the manifestation of a genotype, which can be observed/ influenced by other factors (other gene products, environment or acquired characteristics eg. diabetes)
