Genetics Flashcards
Pharmacogenomics – Recent Advances
Using gene expression data
• Identify new drug targets in people with a condition of interest • Develop new drugs
• New uses for older drugs
• Treatments for certain diseases
• Cystic fibrosis – identified new drug
• HIV – identify those who may be hypersensitive to a particular drug
• Organ transplant – predict dose requirements for immunosuppression
• Preemptive testing
• Test before you need it, have results when needed
Pharmacogenomics in Nursing Practice
• Minimize adverse drug reactions • Ensure appropriate dose for
patient’s genetic profile
• Educate patients & families
• Testing standard of care for more drugs
• May occur preemptively to inform future needs
• Real-world application of precision health
Pharmacogenomics Challenges
- Limited data
- Limited clinical utility of inconclusive results
- Do studies identify effects on clinically relevant outcomes?
- Does pharmacogenomic testing provide valuable information in addition to what is already known from careful clinical assessment?
- Population studied vs. patients seen
- We have a diversity problem in genetics
- Few pharmacogenomic studies identify population(s) studied – likely default is individuals of European ancestry
Breast Cancer
Histologic classifications based on genotyping
• Tumor molecular signatures provide critical information for improving
treatment effectiveness
• Commercially available tests (e.g., OncotypeDx)
• Primary clinical impact
• Adjuvant therapy for early stage disease • Identifying HER2 overexpressing cancers
• Challenge – heterogeneity and complexity
Targeted Treatment for Cancer
- Genotype tumor tissue to identify genetic variants in the tumor
- Develop drugs that target those variants
- Drugs target different aspects of tumor genetics • Block signals that promote tumor growth
- Interfere with cell cycle
- Induce cell death
- Types of therapy
- Small molecules
- Monoclonal antibodies
- Cancer vaccines
- Gene therapy - CRISPR silences mutated cell
- Does not kill normal cells – fewer side effects
CRISPR Cas-9 Gene Editing
• Cancer
• HIV
• Gene therapy for single-gene conditions
• Cystic Fibrosis
• Sickle Cell Disease
• Duchenne Muscular Dystrophy
• Modifying epigenetic state
• Change the epigenetic state→change gene
transcription / translation
• Challenges
• Ethical issues
• Cost
• Accessibility
• Duration of change – can it be sustained?
• What if the target sequence is not a unique sequence in the genome – unforeseen consequences
Direct to Consumer Genetic Testing
Balancing interest with challenges
• FDA approval required – genetic tests are a type of medical device
• Requires a certified lab
• Who can order the tests?
• What testing is done? How comprehensive is it?
• DTC genetic testing for health conditions
• 23andMe approved for 3 BRCA 1/2 mutations and ~10 other conditions
• Some companies offer testing when ordered by a health care provider
• This can be a provider on staff at the company!
• Limited information, education and counseling …mean patients will bring results to their health care providers
Direct to Consumer Genetic Testing
- Educate patient
- Non-diagnostic
- Indicate potentially increased risk
- Confirm test results through CLIA certified lab
- Obtain relevant clinical risk information & family history
- Provide counseling and referral to genetic counselor or genetic specialist, as needed
- Advise against unnecessary follow up
Polygenic Risk Scores
More valuable scores consider the underlying disease
• Does risk vary by age or some other factor?
• How is disease status modeled? Is it continuous (e.g., BP for hypertension) or dichotomous (e.g., diagnosis of cancer)
• Can identify probability of diagnosis, or inform screening approaches
• Integrate risk scores with other information that influences risk (e.g., clinical data, environmental exposures)
Breast Cancer
• Using polygenic risk scores to augment existing risk assessment
• Scores based on many variants, vs. searching for high-risk mutations
in specific genes
• May put some women over the threshold for early screening & other preventive therapies
• More specific than age-related incidence data
Cardiovascular Disease
- 304 identified variants explain ~20% of CAD heritability
- Potential uses
- Identify patients who would benefit most from statin therapy
- Identify patients at risk of poor anticoagulant response (Factor V Leiden)
- Increased risk of venous thromboembolism
- Risk increased with use of certain combined hormonal contraceptives
- Universal screening not cost-effective
- May be beneficial before using second- and third-generation combined contraceptives
Ethical, Legal, and Social Implications
- Ensure patients, families & research participants understand genomics
- Explain what information will be obtained and where it will be stored
- Ascertain interest in testing
- Preferences for receiving results
- Educate patients and families about results • Action able variants
- Incidental findings
- Implications for other family members
- Encourage patients to share results with family members who may be at risk
- Recognize that some family structures & situations are not amenable to sharing results
- Support informed decision-making
- Ensure appropriate referrals for follow-up
- Advocate for access to genetic services
Genetics Has a Diversity Problem
- Vast majority of genetic and genomic studies done in individuals of European ancestry
- Results are not applicable to those with different ancestral backgrounds
- Isolated population groups
- Populations outside of Africa vs. within Africa
- Admixed populations – e.g., individuals who are African American frequently have African and European ancestry due to slavery
- Exacerbates health inequalities
- Inaccurate assessment of pathogenic variants in clinical genomic studies
- Missed opportunities: development of drugs specific to understudied populations
Genetics Has a Diversity Problem
Groups NOT studied will have variants that we don’t see in the groups that ARE studied
• Need to genotype those populations, then apply data to assess population-specific risk
• Consider the impact of environmental & contextual variability
• Self-identified race (e.g., African American) differs from ancestry
• Race is a social construct; ancestry can be ascertained through genetics
Pharmokinetics
Body to drug
