Pharmacogenetics and Personalized Medicine

Question 1

human genome project

Answer 1

• groundwork for understanding similarities and differences between individuals
• next step is determining what it means
• info in OMIM
• total number of human genes much smaller than expected
• despite major phenotypic differences, DNA is 99.5% identical
• differences make us who we are

Question 2

evidence of personalized medicine

Answer 2

1. drug therapy
2. idiopathic disease
3. cancer diagnosis, prognosis, treatment
   4, prenatal testing and newborn screening

Question 3

pharmacogenetics

Answer 3

-relates heritable variation to inter-individual variation in drug response

Question 4

pharmacogenomics

Answer 4

• field of new drug development based on our rapidly increasing knowledge of all genes in the human genome
• pharmacogenetics for profit
• drug design influenced by knowledge of genes
• we need to know genes involved in drug metabolism and effects of different mutations
• individualize drug therapy
• need connections between ADRs and genotypes

Question 5

2 patients

Answer 5

-similar, both have same disease
-both treated with same dug
-3 days later, one ends up in ER and dies
-other has full recovery and feels fine
why?
-genotypes are different
-one is able to metabolize drug and receive benefits

Question 6

four patient groups

Answer 6

• drug toxic but beneficial
• drug toxic but not beneficial
• drug not toxic and not beneficial
• drug not toxic and beneficial
• drugs are marketed as long as there aren’t that many accidental deaths
• 5th/4th leading cause of death
• overall incidence is 6.7%, fatal ADRs are 0.3%
• more than 2 million reactions per year
• 100,000 americans die each year

Question 7

why some drugs don’t work

Answer 7

• genetic variation can influence how quickly a drug is metabolized, how it works or likelihood of side effects
• normal allele CYP2C19*1 results in enzyme capable of converting inactive clopidogrel to active metabolite
• makes blood thinner work
• but abnormal allele means drug remains inactive and doesn’t work

Question 8

how are drugs ok’d

Answer 8

-using averages
-genetic codes are unique though
-

Question 9

genes involved in drug metabolism

Answer 9

• ADME core markers
• absorption, distribution, metabolism ,excretion
• CYP, ABC, SLC, UGT, NAT

Question 10

cytochrome p450 family of genes

Answer 10

• excellent data available
• mutations result in a change in enzymes ability to perform it’s function
• CYP2D6-classes of function are ultra, extensive, intermediate, poor
• normal is extensive- two functional alleles
• poor has no functional allele- need lower dosage
• ultra has duplicate copies- need higher levels
• intermediates are heterozygotes- lower than normal generally needed
• differences among and between ethnic groups

Question 11

mercaptopurine

Answer 11

• for leukemia
• TPMT gene
• can use blood test to determine dosage needed

Question 12

warfarin

Answer 12

• first noticed in the 1920s when cows died from hemorrhage following minor procedures- eating moldy silage containing coumadin
• used in rat poison
• good for humans in proper concentration
• inhibits epoxide reductase- inhibition of vitamin K that is needed for clotting (oxidized form), to complete cycle, oxidized vitamin K is changed back to reduced form by VKOR
• warfarin inhibits VKOR
• reacts with medicines like aspirin, ibuprofen, acetaminophen
• some foods with high vitamin K reduce effectiveness, others increase risk of bleeding
• excessive alcohol may change effect

Question 13

genetic component of warfarin

Answer 13

• some individuals are very sensitive, others are relatively unresponsive
• dosing is trial and error
• can take several months
• can counteract negative effects with vitamin K
• VKORC1 allele accounts for 30% of variation- low dose and high dose groups
• CYP2C9 of cytochrome p450 explains 10% of variability
• polymorphs common in caucasians and rare in african americans and asians

Question 14

oncology

Answer 14

• personalized medicine practiced for years
• each patient evaluated individually, with specific types of tests being ordered that will directly address that patients personal situation

Question 15

diagnosis by microarray

Answer 15

• allows genome wide scan of genetic complement
• chip could be developed that would include a subset of important human genes that would provide actionable info to improve health care
• if study done early, info could be obtained on mutational status for selected genes- could then manage patients health throughout life
• what genes and who decides? if person doesn’t want to know? psychological burden?
• benefits-if treatment is available, early treatment would be possible
• behavior modification- ex high cholesterol

Question 16

microarray testing

Answer 16

-2 brothers, 1.3 MB duplication on 22- 22q microduplication syndrome

Question 17

UPD on microarray

Answer 17

• missing middle band
• when total ROH exceed 5% of genome, likely due to identity by descent (consanguinity, incest, inbred pops, ethnic pops)
• female with 10% ROH– hypotonia, developmental delay, hearing loss, parents are 1st cousins
• expected degree of relatedness was 6.25%, she was 10

Question 18

next gen seq

Answer 18

• personalized medicine
• not enough known at present
• mutations specific to cancer
• currently known set of genes associated with chromosomal microdeletions
• genes commonly associated with birth defects
• the ADME core markers for drug metabolism

Question 19

GINA

Answer 19

• genetic info nondiscrimination act
• federal law prohibits discrimination in health coverage and employment based on genetic info
• provides a baseline level of protection against genetic discrimination for all americans
• if more protective state laws are in place, they will supersede this federal law
• doesn’t cover life, disability, or long term care insurance
• doesn’t apply to businesses with fewer than 15 employees
• doesn’t prohibit health insurer from determining eligibility or premium rates based on presence of disease

Question 20

screening

Answer 20

• testing on a population basis to identify individuals at risk of having or of transmitting a specific disorder
• prenatal, newborn, carrier screening

Question 21

prenatal

Answer 21

-MSAFP, quad test, amniotic AFP

Question 22

newborn screening

Answer 22

• disease-clearly defined and treatable, reasonably high population incidence
• test- large scale, rapid, inexpensive, low false pos, no false neg
• follow up- definitive diagnosis, prompt treatment, genetic counseling
• state based
• testing has to be done, but parents can refuse results

Question 23

carrier screening

Answer 23

• plan is to detect carriers and provide counseling in the hopes that a couple will opt for prenatal testing
• if pre natal testing isn’t available, won’t be tested for carrier status
• key factors:
  1. mutation must be in a reasonably high freq in pop
  2. test is suitable for mass screening
  3. genetic counseling available to explain results to families
  4. prenatal testing available so that when carrier couples are identified it is possible to determine when a pregnancy will result in an affected child

Question 24

carrier screening 2

Answer 24

-tay sachs
-CF
-gauchers
-canavan
-niemann pick
^ Ashkenazi Jew
-beta thal- mediterranean
-sickle cell