L59: Does Genetics Matter? Flashcards
Use of genetics tests in clinical settings
- Diagnostic testing (karyotyping)
- Newborn screening
- G6PD: defective production of glucose-6-phosphate dehydrogenase —> haemolytic anaemia under oxidative stress (Fava beans, antimalarial, sulphonamide, aspirin)
- PKU: lack of phenylalanine hydroxylase —> buildup of phenylalanine
- simple and sensitive test
- identify genetic disorders to be treated early in life
- serious outcome if undetected
- effective treatment available
- common in population - Prenatal diagnosis
- blood test results
- maternal age + gestational age
- chorionic villus sampling / amniocentesis
- affect pregnancy decision (Down’s) - Carrier testing / Asymptomatic (Thalassaemia, cystic fibrosis)
- affect reproductive decision - Predictive genetic testing / Presymptomatic (Huntington’s)
- implied certainty of developing the condition
- controversy: optimal timing for testing, right of parents to test children, confidentiality - Susceptibility testing
Personalised medicine
- Maximise treatment response (HER2)
- Guide dosage
- Minimise adverse effects
- Monitor disease progress
- Prognostic assessment (HER2)
- Disease prevention / susceptibility prediction (BRCA1/BRCA2 carrier, APC gene)
- Nutrigenetics/nutrigenomics
- Toxicogenomics
Examples:
- HER2 receptor in breast cancer
- VKORC1 gene (Vitamin K epoxide reductase complex 1) + CYP450 2C9 gene in warfarin metabolism
- TPMT (thiopurine methyltransferase) genotype in metabolism of 6-mercaptopurine
HER2 (Human Epidermal Growth factor Receptor 2) in breast cancer
- amplification of HER2 gene in 15-20% of breast cancer
- Prognostic implication: higher recurrence + aggressiveness
- Response to trastuzumab (Herceptin): mab bind to HER2 receptor —> stop cell proliferation
Problems of personalised medicine
- Benefits of harm of awareness to genetic risk
- Validity and utility of genetic prediction
- Logistical challenge in preparing for changes
- Ethical, social and legal implications in data handling
- Policy control issues
- Business potential and associated problems
Gene-environment interplay
- Variation in heritability according to environmental circumstances
- Epigenetic effects on gene expression by environment
- Gene-environment interaction
- Gene-environment correlation
- passive (genes and environment passed to offspring)
- active (actively select environment)
- reactive (evoke response from environment)
Benefits and Problems with genetic test results
Benefits:
Positive result: primary prevention, psychological relief
Negative result: relief from worry, free from need for medical surveillance
Problems:
Positive result: gene =/ disease, risk rather than certainty, statistical significance =/ clinical significance
Negative result: negative result =/ no risk, take into account of performance of technology
Problems with test validity
False positive
- unnecessary anxiety, procedure, social discrimination
False negative
- misleadingly reassured
Analytic validity: accuracy of telling DNA sequence
Clinical validity: accuracy of presence of disease
Analytic validity =/ Clinical validity
Single gene disease / Mendelian disease vs Polygenic disease
Simple:
- genotype and phenotype closely correlated
- mutation CAUSE the disease
Complex:
- genotype and phenotype poorly correlated
- mutation PREDISPOSE the disease
Population frequency:
Low, rare, isolated pedigree
High, common, general population
Number of genes required to produce the phenotype:
One
Multiple
Penetrance / participation of individual genes:
High
Low
Environmental influence:
Low
High
Diagnosis / Patient ascertainment:
Family history
Medical screening
Method of detection:
Linkage analysis: detection of disease genes
Association studies / Genome association
Comparison of Traditional genetic testing vs New genomic risk profiling
Disease type:
Rare / Mendelian
Common / complex
Types of variants / alleles:
Coding
Non-coding
Prevalence:
Low
High
Assay type:
Targeted sequencing
Genome-wide arrays
Test result:
Highly predictive
Probabilistic
Individual impact:
High
Low
Population impact:
Low
High
Benefits and Problems with direct-to-consumer testing
Benefits:
- Promote awareness
- Greater access
- Consumer more proactive role
- Improve their health and make lifestyle decision
- Privacy advantage than health care provider
Problems:
- Suitability for indication
- Clinical Validity
- Inconsistencies on which genes are genotyped
- Without guidance, interpretation and follow-up from healthcare provider
- Inaccurate, misunderstood information
- Invasion of genetic privacy in unauthorised way
ACCE framework
A: analytical validity
C: clinical validity
C: clinical utility
E: ethical, legal and social implications
