Lecture 10 - Pharmacogenomics Flashcards
what is an adverse drug reaction?
a negative/undesirable effect of drug treatment, they can influence different systems and are severely debilitating and potentially fatal
the 4th leading cause of death for people who are taking drugs to handle their illnesses
adverse drug reactions
what percent of hospital admissions in the UK have been attributed to adverse drug reactions
6.5%
what are demographic factors that impact response to drugs?
- age
- weight
- sex
8/10 withdrawn drugs affect more ______ than ______
women, men
why do adverse drug reactions occur more in women than men?
women are hugely underrepresented in the research pipeline; pregnancy causes a person to undergo major physiological changes, impacting drug response
drug metabolism and elimination is less efficient in:
newborns and the elderly
how can genetic variation in a gene cause altered enzyme variation?
- regulatory variation
- coding variation
- splice-site variation
regulatory variation influences:
gene expression (increases or decreases)
what are some examples of coding variation?
- missense
- start/stop lost
- inframe insertion/deletion
- stop gained
- frameshift
what are some examples of splice-site variations?
- create/abolish acceptor site
- create/abolish donor site
examines the association between genetic variants and gene expression levels:
expression quantitative trait loci (eQTL)
what is cis eQTL?
genetic variants which impact the gene immediately downstream to it
what is trans eQTL?
genetic variants which impact the gene non-immediately downstream to it
what is the central dogma?
DNA –> RNA –> protein
genetic variations in the coding regions (SNPs, insertions, deletions) can lead to:
changes in protein function
the part of a gene that carries relevent coding information
exons
the part of the gene that does not carry coding information (often regulatory)
introns
in gene splicing defects, parts of the _____ are often retained in the coding sequence
intron
what is pharmacogenomics?
how genetic factors influence drug response
how does the genotype effect drug metabolism?
slow drug metabolism can increase drug toxicity, rapid drug metabolism can lead to a lack of drug efficacy
precision health takes both _____ and _____ factors into account
genetic, non-genetic
often framed as the right treatment, for the right patient, at the right time
precision health
a key pharmacogene which acts as a drug metabolizing enzyme
CYP2D6
CYP2D6 has many genetic variants, including:
single nucleotides variants, duplications, and deletions
codeine is converted to _____ by CYP2D6
morphine
why is it that ultra-rapid drug metabolizers should NOT be prescribed codeine?
they make way more morphine than expected for the given dose
what percent of people carry at least one clinically relevant pharmacogenomic variants
97%
facilitates genotype guided therapy
clinical practice guidelines (ex: Clinical Pharmacogenetics Implementation Consortium (CPIC))
an international consortium which provides systematic grading of evidence and clinical recommendations which aid in genotype guided therapy
Clinical Pharmacogenetics Implementation Consortium (CPIC)
what is myelosupression?
a chemotherapy related adverse reaction characterized by hematological toxicity
how does mercaptopurine work?
mercaptopurine (6-MP) is a purine antagonist and inhibits DNA synthesis/replication, which is cytotoxic (makes it a good cancer drug)
how does thiopurine methyltransferase (TPMT) work?
TPMT catabolizes (breaks down) thiopurines (including 6-MP)
allele frequency differences are linked to:
toxicity
how can drug toxicity be avoided in patients with allele-linked variants?
dose-reductions
TPMT is inactive in some patients, which leads to:
high drug toxicity (unable to breakdown 6-MP)
