08: Personalized Genomics Flashcards
What is pharmacogenomics?
Technology that analyzes how genetic makeup affects an individual’s response to drugs.
It deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug’s efficacy or toxicity.
Aims to develop rational means to optimize drug therapy, with respect to the patients’ genotype, to ensure maximum efficacy with minimal adverse effects.
Such approaches promise the advent of “personalized medicine”; in which drugs and drug combinations are optimized for each individual’s unique genetic makeup.
What is pharmacokinetics?
How the body acts on a drug.
- Liberation
- Absorption
- Distribution
- Metabolism
- Excretion
(LADME)
What is pharmacodynamics?
How a drug acts on the body.
- Binding target proteins
- Stimulating/depressing function of pathways
- Unintended protein interactions
What are purine analogs, and what is their clinical significance?
Antimetabolites that mimic the structure of metabolic purines.
Examples: 6-mercaptopurine, 6-thioguanine, azathioprine
Interfere with nucleic acid synthesis.
Treat lymphoblastic leukeia, autoimmune diseases, inflammatory bowel disease, after organ transplant.
However, their therapeutic utility is limited by adverse events in bone marrow (e.g., mercaptopurine alternatively metabolized by TPMT, leading to marrow toxicity).
TMPT activity varies by person. (GENETICS!)
What is codeine and what is its clinical significance?
A commonly used opioid metabolized into morphine for activity by CYP2D6.
However, 7% of Caucasians have CYP2D6 variant with no activity, thus codeine never metabolized.
What is Warfarin and how is its dosage affected by genetics?
A widely used drug for anticoagulation.
Has a narrow therapeutic range with dosing impossible to predict beside through trial-and-error.
Three genes affect dosing: CYP2C9, VKORC1, CYP4F2.
Genetic prediction models could help increase accurate dosing.
What is relative risk and how do you calculate it?
Ratio of the probability of an event occurring in an exposed (has genetic variant) group to a non-exposed group.
P(V|D) / P(V|H)
where…
P(V|D) is proportion of diseased with variant
P(V|H) is proportion of healthy with variant
How is multivariant analysis used in genetics?
Whereas GWAS uses univariate association analysis (one gene at a time), multivariant analysis can reveal population genetic structure and high-order genetic signature of disease.
This information is taken and mathematically transformed via Principal Component Analysis to fit the first principle component along the dimension with the highest variance, 2nd dimension second most, etc.
What are novel variants, and how many does each person have?
Variants that are only your own, not shared by anyone else on the planet.
Each individual is estimated to have 50-100 novel variants.
