Pharmacogenomics Flashcards
adverse drug reactions
negative/undesirable effects of drug treatment
influence different systems
severely debilitating and potentially fatal
response to medications
multi-factorial:
demographic factors - age, weight, sex, ethnicity
clinical factors - liver and kidney function, concomitant medications
dosing factors - formulation, route, regimen
other factors - adherence, food intake
contribute to variable medication exposure → no drug response, therapeutic response, drug toxicity
ethnicity
proxy for genetic factors; environmental factors ex. diet
examples:
- african-americans increased risk of heart failure from hydralazine
- east asian descent alcohol metabolism
sex and variation in drug response
8-10 withdrawn drugs effect women more than men
women are underrepresented in research
→ pregnancy - physiological changes; relevant for both mother and fetus
age and variation in drug response
newborns, elderly
body composition changes (fat and BMI); polypharmacy
renal excretion → glomerular filtration rate lower in neonates (also declines after 20) = longer to excrete drugs
drug metabolism → changes in enzyme expression levels; CYPs and phase II conjugating enzymes; disease of metabolic organs - kidney/liver
pharmacogenetics
pharmacokinetic and pharmacodynamic variation
integrates genetics with other factors to address where on the spectrum an individual falls
genetic variation
alter enzyme activity
1. regulatory variation
2. coding variation
3. splice-site variation
regulatory regions
change in the region can lead to increased/reduced expression of genes
association between genetic variants and gene expression levels
- mutation that affects transcript levels: expression quantitative trait loci (eQTL)
- can be cis (affect immediate gene downstream) or trans (affect other genes)
coding regions
variation within the coding regions can be a SNP, a deletion, or an insertion
splicing regions
introns are cut out - coding region is just exons
mutation that reads a site as a splice region = splicing defect → impact amount of functional enzyme made (shift the reading frame)
pharmacogenomics
influence on drug response → drug response is heritable (coded in DNA); key determinant of response to mediation
gain insight into disease pathophysiology
precision health
accounts for both genetic and non-genetic factors
drug dosing algorithms
the right treatment, for the right patient, and the right time
CYP2D6
pharmacogene
important drug metabolizing enzyme
polymorphic = susceptible to mutations (100+ variants)
SNPs, large scale duplications and deletions
genotype effects on drug metabolism
maximal benefit - fall within therapeutic range
duplications of metabolizing enzyme gene → break down drug too fast = no sufficient effect
deletions → break down slower = drug toxicity
codeine/CYP2D6 pharmacokinetics
codeine is converted to morphine by CYP2D6
ultra-rapid metabolizers who are breastfeeding should not be prescribed codeine
too much morphine will pass into breast milk = child consumes the morphine
clinical relevance
97% of individuals carry at least one clinically relevant pharmacogenomic variant
most likely won’t take the associated medication
consideration for pharmacogenomic biomarkers → associations between genetic variants and adverse drug reactions; reliable replication; phenotyping
clinical practice
genotype guided therapy
clinical pharmacogenetics implementation consortium: systematic grading of evidence and clinical recommendations
gene-drug pair examples
thiopurines → NUDT15 and TPMT
anticancer (cisplatin) → TPMT
cisplatin
cancer treatments cause severe ADR → childhood cancer
cisplatin-induced hearing loss (40-60% affected)
genetic variants in TLR4
TLR4 variant
alters its expression in response to cisplatin
eQTL → regulatory
variants in TLR4 promoter impacted expression of reporter enzyme
addition of cisplatin = decrease in amount of non-mutated genes produced → promoter decreased expression
= inhibition of TLR4 can protect against cisplatin-induced hearing loss
chemotherapy-related adverse reactions
myelosuppression
mucositis
ototoxicity
sterility
nephrotoxicity
peripheral neuropathy
alopecia
nausea
cardiotoxicity
pancreatitis
mercaptopurine
guanine analog
purine antagonist inhibits DNA synthesis/replication = cytotoxic
ADRs: hemotological toxicity (myelosuppression)
PGx - 6-MP
TPMT: thiopurine methyltransferase gene
catabolizes thiopurines - 6-MP
NUDT15: metabolism of cytotoxic thioguanine nucleotides
alleles in both genes → toxicity
normal breakdown doesn’t work = higher drug levels → kill healthy cells = myelosuppression
genotype guided dosing
wt - normal metabolism = reduced levels of drug
heterozygotes - intermediate level
complete loss of function - no metabolism = spiked drug levels
adjust drug dosage according to genotype = drug levels are homogenized across patients - decrease toxic effects
