Ethnicity and pk Flashcards
What is pharmacogenetics (PGx)?
- Pharmacogenetics and Pharmacogenomics are the same thing
- Study of how genetic differences between patient’s account for differences in their response to drugs
- Genes make proteins which can influence pharmacodynamics/pharmacokinetics
What is genetic variation
- Random mutations drive evolution
- Most variation is due to single nucleotide polymorphisms (SNP)
- SNPs lead to different alleles (variant form of genes)
How do SNPs effect PK of a drug?
• Effects genomic sequence, so different enzymes/receptor is different
WARFARIN example
- Blood thinner
- Broken down by cytochrome P450 enzyme, CYP2C9
- Different polymorphism 1, 2 & 3
- Only type 1 works
- 2 & 3 are inactive, reducing metabolism leading to higher warfarin concentrations
CLOPIDOGREL example
- Prevents platelet aggregation
- Pro-drug so needs to be metabolised to active metabolite
- Metabolised by CYP2C19
- Mutation can cause CYP2C19 to be inactive or lower activity
- So higher risk of clotting (higher in black and Asian patients)
Types of pharmacogenomic studies?
- Gene-drug pair studies
- GWAS studies
- Polygenic risk scores
What is gene-drug pair?
- A Drug-Gene Interaction (DGI) is an association between a drug and a genetic variant that may affect a patient’s response to drug treatment.
- Risk prediction
- Prevent ADRs
- Optimises dosage and medication
- EXAMPLE – warfarin cyp2c9
What is GWAS studie
• Genome-wide association study
• An approach used in genetics research to associate specific genetic variations with particular diseases
• hundreds of thousands to millions of genetic variants
across the genomes of many individuals are tested to
identify genotype–phenotype associations
• Looking for associations between genes and disease (population based) – need huge population size for these studies
• DEFINITION – An approach used in genetic research to associate specific genetic variations with particular diseases
GWAS pros and cons
- Used in medicine, agriculture, wildlife
- Used to look for variation in an entire genome
- It allows scientists to uncover more consistent genetic trends throughout a study population
PROS
• No need for candidate gene
• Do not have to assemble fragments of a genome – can see full range at once
• Provides insight into genetically associated traits that then allow scientists to better manage these traits
CONS
• Associations are sometimes very weak
• ‘Newer technology’ – many more advances to be made – need to improve accuracy
• Has to be done using advanced machines and at specific labs
• Time consuming process
• Expensive
GWAS study design
- Identify many individuals (peoples, trees, etc.) that have detectable differences (different traits/phenotypes)
- Search across the entire genome for base-pair differences, i.e. where the genotypes have different A/C/G/T
- Try to find where there is a consistent difference in the genome – where are the base pairs consistently different when a specific trait is present?
- If successful, able to focus on a place/region in the genome that must be involved in this difference
- Don’t have to guess ahead of time what kind of gene you’re trying to find/where the gene is in the genome
Polygenic risk scores
• Looking at genetic tests to predict risk of e.g., cardiovascular disease etc
DPYP and chemotherapy pharmacogenetics
- 5-fluorouracil (5FU) or capecitabine most commonly used drugs to treat cancers (breast, head and neck, anal, stomach and colon)
- Can have life threatening toxic effects
- DPD protein which is essential to process the 5FU or capecitabine during cancer treatment
- DPD stands for dihydropyrimidine dehydrogenase. It is an enzyme made by the liver that helps our body break down thymine and uracil.
- The DPD enzyme helps our body to break down 5FU, capecitabine
- Without enough DPD the 5FU or capecitabine builds up causing more severe toxic effects than usual
- Several SNPs have been identified in DPYD gene that cause the toxic effects of 5FU or capecitabine
- DPD deficiency is caused by mutations in the DPYD gene
What is RACE?
• Race is understood by most people as a
mixture of physical, behavioural and cultural
attributes
What is ethnicity?
• Ethnicity recognizes differences
between people mostly on the basis of language
and shared culture
What is allelic frequency?
• An allele frequency is calculated by dividing the number of times the allele of interest is observed in a population by the total number of copies of all the alleles at that particular genetic locus
