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Pharmacogenetic and Pharmacogenomic Biomarkers - Coggle Diagram
Pharmacogenetic and Pharmacogenomic Biomarkers
Useful definitions
Pharmacogenetics
Study of how genetics influences drug response. Typically one or few genes are considered
Pharmacogenomics
Study of how genomic variability influences drug response, considering the whole genome
Pharmaco-omics
Uses data from genomics, transcriptomics, proteomics, metabolomics, epigenomics... to evaluate drug response
Pharmacodynamics
Pharmacokinetics
(
A
)
ADME
They can be studied through the
PK/PD curve
(effect (y) as a function of time (x))
Clinical potential
Stratification
of patients
based on predicted response to therapy
to administer the
best drug
at the
most effective dosage
Development of genetic biomarkers in clinical trials
Prospective
biomarker analysis
Patients are first
stratified based biomarker status
. Then, each subgroup is randomized for treatment, and eventual diversity in response is evaluated
Retrospective
biomarker analysis
A potential marker is evaluated by analyzing data from
previously conducted clinical trials
. If variability across drug responders is witnessed, samples from patients are genotyped to find allelic variants responsible for such diversity
Steps for establishing Pharmacogenomic indications in the clinic:
Discovery
of a genetic polymorphism affecting drug response
Clinical validation to evaluate the
predictive accuracy
of genetic testing
Health technology assessments
to establish
cost-effectiveness
for healthcare systems
Establishing of an
accredited clinical genomics pipeline
Development of a
genetic counseling framework
Training
current and future clinicians to genetic-guided pharmacology
Set the
regulation
framework
Influence of
genetic variability
on PK/PD, which leads to
differences in therapy efficacy/toxicity
Drug transporters
Influence PK/PD
Drug metabolizing enzymes
Influence PK
Many enzymes involved in hepatic metabolism are polymorphic (ex. CYP450)
Drug targets
Influence PD
Besides genetics, other factors can influence PK/PD
Intrinsic
Age, pregnancy, other diseases, ethnicity, sex
Extrinsic
Diet, smoking, environment, medical interventions, microbiome
FDA Pharmacogenomic markers
Genetic testing recommended
Actionable PGx
Genetic testing required
Informative PGx
Provide information on whether genetic testing is required before starting therapy to predict responsiveness
Examples of
genetic tests in clinical use
CYP2D6 polymorphisms
for
antidepressants
and
antipsychotics
CYP450 family members (1, 2, 3) are the most important
detoxifying enzymes
for both endogenous substrates and xenobiotics, like drugs
Multiple CYP450 isoforms whose activity can be influenced by polymorphisms, induction, age, sex, inflammation
CYP2D6
metabolizes
20% of drugs
Its activity is influenced by:
Inflammation
Polymorphisms
Poor metabolizers
Adverse effects and toxicity, as the drug concentration remains very high
Intermediate metabolizers
Exaggerated response
Extensive metabolizers
Expected response
Ultrarapid metabolizers
Lack of response and therapy failure
This depends on
gene duplication
events. Multiple CYP2D6 can be present
Different allele frequencies in different
ethnicities
Drug dose
should be
tailored to the patient's profile
by taking these parameters into consideration
CYP450 variants can be detected through
gene expression profiling
Roche Amplichip CYP450
Microarray platform
for the detection of
CYP450 variants
. Offers broad coverage of known variants for many ethnic groups. Focuses particularly on family 2, to which CYP2D6 belongs
Results used to adjust therapeutic regimen
Warfarin
Applications
Treatment of blood clots to prevent thrombosis/stroke
Mechanism of action
Inhibition
of the
enzyme converting vitamin K to its active form
(
VKOR
, Vitamin K Epoxide Reductase). Vitamin K is used to form blood-clotting proteins that hold together blood cells to form clots
Potential adverse effects
Excessive bleeding
Dosage should be carefully evaluated
Algorithms
are available to evaluate the dosing based on genetic information and other intrinsic and extrinsic factors
WarfarinDosing
Narrow range between efficacy and toxicity
Genetic variability explaining different response to Warfarin
VKORC1
(gene coding for VKOR)
polymorphisms
Account for the majority of variability in Warfarin response
CYP29C
(metabolizing enzyme)
polymorphisms
leading to a
reduction
in its
metabolizing activity
Lower Warfarin dose required for these patients to avoid serious bleeding events
This explains about 20% of variability in Warfarin response
GWASs for the identification of genetic variants associated with Warfarin response
Workflow:
Divide patients based on response to drug (as a quantitative or binary trait)
DNA samples collection
GWAS for the identification of SNPs associated with differential Warfarin response
One study identified only VKORC1 + CYP2C9, another also identified CYP4F2 (1-2% of variability)
Benefits of pharmacogenetics analysis before starting Warfarin treatment
Reduction of time necessary to reach the therapeutic dosage
Reduction of bleeding events
IL28b and HCV therapy
Pegasys
Provides one of the best examples of how GWAS can identify genetic variants involved in differential response to therapy
Therapy for
HBV
and
HCV
consisting of
PEGylated Interferon alfa-2a
Response to therapy is highly variable, especially in African Americans
4 GWASs
reported an association between
IL28b SNPs
and
differential response to Pegasys
Such SNPs vary much across ethnicities, explaining 50% of ethnic variability in therapy response
IL28a variants are involved because this gene codes for
IFN-gamma
, involved in
antiviral response
. Variants of IL28b can therefore introduce variability in the IFN-gamma production and the subquent activation of cell-mediated IS response
Examples of how
GWASs
can help predict response/adverse effects
Predicting
Covid-19 vaccines adverse effects
GWAS of adverse effects
reported
HLA-A 03:01 variant
is associated with stronger side effects
The
higher
the
CN of HLA-A allele
, the
higher
the
risk of severe side effects
MAF = 0.15 in Caucasians
The association of HLA-A variation with severe side effects depends on the kind of vaccine (Pfizer/Moderna)
Probably, HLA-A variant is associated to stronger side effects when Pfizer vaccine is administered because Pfizer vaccine elicits a stronger CD8+ response compared to Moderna. Instead, Moderna vaccine activates much the innate IS response
This HLA-A variant activates CD8+ T cells more strongly, leading to severe side effects
Response to
statins
Multiple GWASs identified that
gene variants
associated with
disease phenotype
could also play a role in
influencing the response to therapy
("
pharmacogenes
")
Studies have shown that the
impact size
of
pharmacogenetic variants
is typically
much larger
than disease susceptibility variants
Drug exposure is a recent phenomenon in human evolution, so the extreme/more impacting pharmacogenetic variants haven't been subjected to negative selective pressure yet
In complex traits, phenotypic differences between individuals with different genetic variants are minimal. Instead, pharmacogenetic variants may be associated to more drastic differences (responder/non responder)
Use of more carefully measured and controlled phenotype data in studies
Easier to obtain results when performing PGx GWASs
Comparison between
drug metabolism PGx
and
drug target PGx
Drug target PGx
Smaller distinction between phenotypes
Phenotypes may not be easily measured accurately
Polymorphisms have smaller functional effects and do not result in LOF
Drug metabolism PGx
Larger distinction between phenotypes
Phenotypes easily measured
Polymorphisms lead to non-functional proteins
Not only can PGx be studied through GWAS, but also through
WGS/WES
Sequencing allows the identification of
rare variants
, which are likely accounting for a substantial share of variability in drug response
For some genes with minor contribution to the disease,
rare variants explain 100% of their contribution
to differential drug response
GWASs cannot give the full picture because rare, but impactful variants are missed
Databases
PharmGKB
Stores genotyping data and correlates them with phenotypic measures of drug response. Offers guidelines to implement this information into clinical practice
CPIC
Consortium whose aim is to facilitate the use of pharmacogenetic tests in the clinic
PharmVar
Central repository for pharmacogenetic variations
Direct To Consumer
(
DTC
) PGx tests
They are offered by private companies to patients to test for the presence of genetic variants that may influence the patient's response to therapy
Example:
23andMe
Good sensitivity and specificity, but high risk of false negatives
FDA-approved DTC PGx test