Week 6: Precision Medicine

Q: What is the goal of precision medicine in drug treatment?

A: To select drugs based on a patient's individual characteristics rather than trial and error.

Q: Why is the trial-and-error method insufficient?

A: Not all patients benefit, and some experience adverse effects.

Q: How does genetic classification improve treatment?

A: It allows personalized drug choices tailored to a patient’s molecular profile

Q: What determines the best breast cancer treatment?

A: Molecular type: ER+/PR+, HER2+, or Triple-negative.

Q: Which breast cancer type benefits most from standard chemotherapy?

A: Triple-negative breast cancer. Because nothing that it can specifically target like estrogen/progesterone receptors or HER 2

How to treat ER+/PR+ most specifically 

Tamoxifen (binds to estrogen receptor causing proliferation of these cells)

How to treat HER2 most specifically?

Trastuzumab (Herceptin)(prevents from sending growth and proliferation signals)

Q: What is pharmacogenomics?

A: The study of how genes and DNA variants influence disease and drug response.

Q: Why are polygenic diseases harder to study?

A: They involve many genes contributing small effects.

Q: What does a GWAS (Genome-Wide Association Study) identify?

A: SNPs(single nucleotide polymorphis) associated with disease that are common in patients and uncommon in non-patients.

Q: What does the Manhattan plot display in GWAS?

A: Each dot represents an SNP; those above the significance line are candidate SNPs for investigation.

What is a SNP

single nucleotide polymorphisms

Q: What is a polygenic risk score?

A: A score representing cumulative risk based on multiple disease-associated SNPs

Q: How can polygenic risk scores help patients?

A: They guide preventive advice like yearly screenings or lifestyle counseling.

Q: What are the main steps after identifying candidate SNPs?

A: Validate genes in the lab, study gene-gene interactions, create risk scores, and inform patients/physicians. Then can use to make clinical decisions. 

Q: Why is cost an important factor in precision medicine testing?

A: Sequencing ranges from one gene to whole genomes, with varying costs.

Q: Why consider the cost of adverse events?

A: Avoiding severe side effects can save money and improve patient safety.

Q: Why might insurance companies be reluctant to cover sequencing?

A: Benefits may appear years later, possibly after the patient has switched insurance.

Q: What risk comes with direct-to-consumer genetic testing?

A: Patients may misinterpret results without professional guidance. Genetic results can cause fear, confusion, or life-altering decisions.

Q: Why did Claire seek ApoE4 testing?

A: Family history: great-grandmother, grandmother, and mother had Alzheimer's.

Q: What difficulty did Claire face when seeking testing?

A: Turned away by multiple physicians because she had no symptoms.

Q: What happened after she got her results?

A: Received results without counseling, felt devastated, moved to a state with legal physician-assisted suicide.

Q: How did Josh learn he had two copies of ApoE4?

A: Through a workplace genetic testing study.

Q: Why did Josh struggle after receiving his results?

A: Felt unprepared; little medical guidance beyond “diet and exercise.”

Q: Why did Josh criticize direct genetic testing?

A: Believed it was unethical to give people alarming results with no actionable medical treatment.

What is V on here

Variants on the SNPs

Q: What does ApoE do in the body?

A: Helps cholesterol particles dock and distribute lipids to cells.

Q: Which lipoprotein carries ApoE for healthy lipid regulation?

A: HDL (good cholesterol).

Q: How does ApoE2 affect Alzheimer’s risk?

A: Decreases risk (protective).

Q: How does ApoE2 affect cardiovascular risk?

A: Increases risk for early CVD due to having C158 (as opposed to standard R158) which inhibits receptor binding

Q: How does ApoE3 affect Alzheimer’s risk?

A: Neutral/average risk.

ApoE3 Alleles

R158, C112

ApoE2 Alleles

C158, C112, 

ApoE4 Alleles

R158, R112; R112 variant causes interaction between C255 and R61

Q: How does ApoE3 affect cardiovascular risk?

A: Neutral/average risk.

Q: How does ApoE4 affect Alzheimer’s risk?

A: Greatly increases risk in a dose-dependent manner.

Q: How does ApoE4 affect amyloid-β (Aβ) in the brain?

A: Worst clearance; because it promotes very low density lipoprotein binding instead of standard high density lipoprotein binding

Apolipoprotein E image

Q: Risk of Alzheimer’s with 0 copies of ApoE4?

A: ~9%.

Q: Risk of Alzheimer’s with 1 copy of ApoE4?

A: ~30%.

Q: Risk of Alzheimer’s with 2 copies of ApoE4?

A: Up to ~90%.

Q: How many Americans have 1 copy of ApoE4?

A: ~75 million.

Q: How many have 2 copies of ApoE4?

A: ~7 million.