Personalized medicine Flashcards
Reasons for genetic testing
- Likelihood of developing disease
- Choosing the most appropriate drug
for treatment
• Pharmacogenomics &
personalised medicine - Legal
- Ancestry
Pharmacogenomics (PGx) – treatment regimens
• The aim is to leverage an individual’s genomic data to the treatment of disease so that: 1. The right drug is prescribed 2. The correct dose and dosage schedule is determined 3. Avoid adverse side effects • Drugs are not equally effective in all individuals • Some people respond more favourably over others
Pharmacogenetics example
CYP2D6 gene
• CYP2D6 gene encodes debrisoquine hydroxylase, expressed primarily in the liver • Responsible for the metabolism of 25% of drugs (such as paracetamol & codeine) • There are 70 different CYP2D6 alleles
Pharmacogenomics - Targeted therapies
Use genomic data to develop targeted therapies to suit the unique genotype of the individual • ~25% of breast cancers showed HER-2 overexpression • Correlated with increased invasiveness • Herceptin® mAb blocks HER-2 signalling • Partially successful – problem heterogenicity of tumor genotypes**
Genotyping
• Detects SNPs over entire genome or in targeted
genomic regions
• Allows for the identification of SNPs that have been
associated with particular diseases*
• *determined from prior GWAS study (studies)
• Can screen for a lot of markers at once (4 million or so)
Whole-genome sequencing
• Provides context to the genetic variations observed
• Provides entire genome sequence to analyse
• Allows for the identification of ‘rare’ mutations not previously characterised
• Typically completed using Next-generation sequencing (NGS)
• Several different technologies exist, with new ones
emerging
NGS vs genotyping
NGS Complete information All variants may be identified (incl rare / new) Expensive (in comparison) Diagnosis
Genotyping Partial information Only identifies known variants Cheaper (in comparison) Slower (in comparison)** Rapid (in comparison) Determination of risk (disease prevention)
NGS outlook
• Costs per genome coming down
• Technologies developing greater throughput
• Leading to the NGS revolution
• Power of NGS in healthcare is determined by size of our datase
Towards WGS implementation in healthcare
Current focus on rare diseases
GWAS analysis
Manhattan plot Each ”dot” is a SNP, reported based on its p value for association Threshold for GWAS significance (5 x 10 -8)
Polygenic risk scores (PRS)
• A measure of an individual’s liability for a particular phenotype (disease)
• Based on GWAS data
• Confers a degree of ‘weight’ to the predictive power of NGS or genotyping data for an individual
• Individuals with a higher weighted PRS may be more likely to develop the trait
• Limited by the size / source of the dataset – mostly European (at
present)
Liability
Liability is a term used to collectively describe all the genetic and environmental factors that contribute to the development of a multifactorial disorder.
Clinical utility of PRS
Potential to impact clinical practice (and related fields) and the management of complex diseases to the same extent as WGS in the diagnosis of rare diseases
• Will be even more accurately derived when WGS cost reaches that of
genotyping (ie WGS replaces genotyping)
• Redirect resources from treatment to prevention in complex diseases
(from ”diagnose and treat” to ”predict and prevent”)
Direct to consumer (DTC) genetic testing
DTC refers to a genetic test you can complete at home
without a healthcare provider, doctor prescription.
• You collect a DNA sample and send it to the company.
• They analyze it and produce a report on your genetics
• There are many different types of tests available for:
o ancestry
o kinship
o lifestyle/health factors
o disease risk
DTC genetic testing vs traditional medical testing
test initation DTC: patient Traditional; healthcare worker Quality control: DTC:test quality largely unregulated traditional: regualted, quality system Data interpretation regulation Traditional: data interpreter are licensed
Ethical implications of DTC genetic testing
- Do you want to know?
• If the trait has no known cure / treatment, would you want to know? - Reliability of data for non-European populations
• Limitations of PRS - Individuals may be unprepared for the results
• What if the report returns an unexpected finding? Where can the consumer seek more information / treatment options
• Increased load on clinicians - Who should know the results?
• Are relatives / life partners entitled to know the results of the test, if it
has the potential to effect them? - Privacy concerns
• What safeguards are in place to prevent employers / insurance providers / etc from obtaining the results?
