Pharmacogenomics

Question 1

adverse drug reactions

Answer 1

negative/undesirable effects of drug treatment
influence different systems
severely debilitating and potentially fatal

Question 2

response to medications

Answer 2

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

Question 3

ethnicity

Answer 3

proxy for genetic factors; environmental factors ex. diet

examples:
- african-americans increased risk of heart failure from hydralazine
- east asian descent alcohol metabolism

Question 4

sex and variation in drug response

Answer 4

8-10 withdrawn drugs effect women more than men
women are underrepresented in research

→ pregnancy - physiological changes; relevant for both mother and fetus

Question 5

age and variation in drug response

Answer 5

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

Question 6

pharmacogenetics

Answer 6

pharmacokinetic and pharmacodynamic variation
integrates genetics with other factors to address where on the spectrum an individual falls

Question 7

genetic variation

Answer 7

alter enzyme activity
1. regulatory variation
2. coding variation
3. splice-site variation

Question 8

regulatory regions

Answer 8

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)

Question 9

coding regions

Answer 9

variation within the coding regions can be a SNP, a deletion, or an insertion

Question 10

splicing regions

Answer 10

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)

Question 11

pharmacogenomics

Answer 11

influence on drug response → drug response is heritable (coded in DNA); key determinant of response to mediation

gain insight into disease pathophysiology

Question 12

precision health

Answer 12

accounts for both genetic and non-genetic factors
drug dosing algorithms

the right treatment, for the right patient, and the right time

Question 13

CYP2D6

Answer 13

pharmacogene
important drug metabolizing enzyme
polymorphic = susceptible to mutations (100+ variants)

SNPs, large scale duplications and deletions

Question 14

genotype effects on drug metabolism

Answer 14

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

Question 15

codeine/CYP2D6 pharmacokinetics

Answer 15

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

Question 16

clinical relevance

Answer 16

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

Question 17

clinical practice

Answer 17

genotype guided therapy
clinical pharmacogenetics implementation consortium: systematic grading of evidence and clinical recommendations

Question 18

gene-drug pair examples

Answer 18

thiopurines → NUDT15 and TPMT
anticancer (cisplatin) → TPMT

Question 19

cisplatin

Answer 19

cancer treatments cause severe ADR → childhood cancer
cisplatin-induced hearing loss (40-60% affected)
genetic variants in TLR4

Question 20

TLR4 variant

Answer 20

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

Question 21

chemotherapy-related adverse reactions

Answer 21

myelosuppression

mucositis
ototoxicity
sterility
nephrotoxicity
peripheral neuropathy
alopecia
nausea
cardiotoxicity
pancreatitis

Question 22

mercaptopurine

Answer 22

guanine analog
purine antagonist inhibits DNA synthesis/replication = cytotoxic
ADRs: hemotological toxicity (myelosuppression)

Question 23

PGx - 6-MP

Answer 23

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

Question 24

genotype guided dosing

Answer 24

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