Unit 7 - Personalized Medicine and Pharmacogenomics

Question 1

pharmacogenetics VS pharmacogenomics VS pharmacokinetics

Answer 1

genetics: heritable variation to inter-individual variation in drug response
genomics: field of new drug development based on rapidly increasing knowledge of all genes in human genome
kinetics: study of mechanisms of absorption and distribution of an administered drug

Question 2

why don’t some drugs work in some patients?

Answer 2

the normal “wild type” allele has normally functioning enzymes that respond to medications appropriately
-mutations in any one part of the pathway will cause changes and different outcomes, so mutant protein is unable to interact with drug properly, causing either no effect or ill effect

Question 3

what is drug design influenced by?

Answer 3

genetics

Question 4

what are the ADME core markers? the most well known?

Answer 4

genes involved in drug metabolism; most well known are CYP450

• absorption
• disruption
• metabolism
• excretion

Question 5

what are the different classes of function of CYP2D6 and their number of functional alleles?

Answer 5

1. poor - 0 functional alleles (very low level of enzyme activity, so slow conversion process, and may be ineffective)
   - drug accumulation may be toxic, so need lower doses
2. intermediate - 1 allele (heterozygote with 1 mutant, 1 normal; can use drug at a slower rate, so need lower doses to avoid toxicity)
3. extensive - 2 alleles (normal; work in expected fashion, and group that must drugs target)
4. ultra - more than 2 alleles (duplicate copies, and degrade drug so rapidly that it’s eliminated before effect takes place; need higher doses or other drugs)

Question 6

are there ethnic differences in frequencies of classes of drug response?

Answer 6

yes

Question 7

what is the mechanism of warfarin?

Answer 7

inhibits epoxide reductase (Vitamin K reductase)

• prevents oxidized K from becoming reduced K, which activates the clotting cascade
• so warfarin will prevent clotting, as constant reduced K is needed for clotting

Question 8

what are downsides to using warfarin?

Answer 8

1. reacts with many common medicines like antibiotics, aspirin, ibuprofen, and acetaminophen (increased risk of bleeding)
2. eating lots of vit K will reduce effectiveness, but other foods (ginger, garlic, etc.) will increase risk of bleeding
3. excessive alcohol use changes effects

Question 9

how is the proper amount of warfarin found in patients?

Answer 9

trial and error; initially give normally benign dose and see if it’s effective (keep), ineffective (increase dose), or negative effect (decrease dose and give vit K)

Question 10

what are 2 genes that directly affect warfarin metabolism?

Answer 10

1. VKORC1 allele of VKOR gene - 30% of variation
   - low dose (more sensitive - Asians) VS high dose (more resistant so need higher dosage - Blacks)
2. CYP2C9 allele of Cyt P450 - 10% of variation
   - polymorphisms most common in Caucasian, and rare in Blacks and Asians

Question 11

what are the different warfarin doses for the VKORC1 1173 genotype if:
CC
CT
TT

Answer 11

CC (37%) - 6.2 mg/dL
CT (47%) - 4.8 mg/dL
TT (16%) - 3.5 mg/dL

Question 12

what is one specialty where personalized medicine is constantly used?

Answer 12

oncology

• patients are evaluated individually, with specific types of tests ordered that directly address patient’s personal situation
• all data are collected and combined to provide unique characterization

Question 13

how is microarray technology used? what can it detect?

Answer 13

genome-wide scan of a person’s genetic complement

• gene chip may be developed to include subset of important human genes, including mutations
• -need to decide what genes on chip
• can detect uniparental disomy, regions of homozygosity

Question 14

what is expected in offspring of cosanguine patients?

Answer 14

expected ROH 6.25% (+/- 2.43) with several hundred genes

Question 15

what are the different identity by descents?

Answer 15

1. consanguinity
2. incest
3. inbred populations - geographically isolated
4. ethnic populations

Question 16

what is needed info for next generation sequencing?

Answer 16

1. mutations specific to one+ cancer categories
2. currently known set of genes associated with Xmal microdeletions
3. genes commonly associated with birth defects
4. ADME core markers for drug metabolism

Question 17

what does the Genetic Information Nondiscrimination Act (GINA) do? not do?

Answer 17

Does

• prohibits insurers or health plan administrators from using genetic info in decisions about coverage or rates
• prohibits employers from using genetic info for hiring, firing, or promoting decisions

Does not

• cover life, disability, or long-term care insurance
• apply to businesses with <15 employees
• prohibit a health insurer from determining eligibility or premium rates based on disease presence

Question 18

what are the three different categories of screening?

Answer 18

1. prenatal screening
2. newborn screening (affecteds)
3. carrier screening (phenotypically normal, but at risk for affected child)

Question 19

newborn screening

• disease
• test
• f/u

Answer 19

disease: clearly defined and treatable, with reasonably high population incidence
test: large scale, rapid, and inexpensive, with low false positives and no false negatives
f/u: if definitive diagnosis, can provide prompt treatment, and there is genetic counseling available

Question 20

what are key factors in carrier screening?

Answer 20

1. mutation must be in a reasonably high frequency in population
2. test is suitable for mass screening
3. genetic counseling is available to explain results to family
4. prenatal testing is available so that when carrier couples are identified, it’s possible to see if pregnancy will result in affected child

Question 21

what are the 5 main disorders that are high frequency in Ashkenazi Jews?

Answer 21

Tay-Sachs
Cystic fibrosis
Gauchers
Canavan
Niemann-Pick

Question 22

what is the disorder that is high frequency in Mediteranian community?

Answer 22

beta-thalassemia