Pharmacogenomics + Pharmacogenetics

Question 1

CYP2D6

Answer 1

Pharmacogenetic phenotype- PHARMACOKINETIC

-enzyme that metabolizes about 25% of all meds

Question 2

CYP2C9

Answer 2

Pharmacogenetic phenotype- PHARMACOKINETIC
-metabolism of many drugs - ESP KNOWN FOR METABOLISM OF WARFARIN

-some people are poor metabolizers=hgih warfarin levels = bleeding complications

Question 3

CYP2C19

Answer 3

Pharmacogenetic phenotype- PHARMACOKINETIC

• chinese and japanese have this = greater cure rate bc more activity of the drugs
• proton pump inh inactivators (omeprazole and iansoproazole)

Question 4

TYMS

Answer 4

• pharmacogenetic phenotype - RECEPTOR/TARGET:
• thymidylate synthetase
• methotrexate - anticancer or immunosuppressive inh methionine and DNA synthesis
• indel occurs where promoter enhanced for TYMS = inc breakdown of methotrexate = dec efficacy and poorer prognosis

Question 5

ERalpha

Answer 5

• pharmacogenetic phenotype - RECEPTOR/TARGET: ESTROGEN RECEPTOR alpha
• polymorphism in the intron between the 1st and 2nd exon of the ERalpha gene
• homozygotes for the less common (c/c) allele had a greater inc in HDL levels following HRT

Question 6

APOE

Answer 6

• pharmacogenetic phenotype- INDIRECT: Apolipoprotein E
• lipoprotein found in chylomicrons VLDL, IDL, and HDL
• absence of certain allelesin the APOE gene corelate with better than therapeutic success for alzheimers disease therapy with tacrine

Question 7

KCNE2

Answer 7

• pharmacogenetic phenotype- INDIRECT: Potassium channel sub-unit
• 1.6% of population are variants
• antibiotic therapy (clarythromycin) can induce prolonged QT interval
• result in a deadly cardiac arrhythmia

Question 8

OCT1

Answer 8

-hepatic transporter that mediates the uptake of organic cations

Question 9

pharmacogenetics definition:

Answer 9

study of the genetic basis for variations in drug response

Question 10

pharmacogenomics definition:

Answer 10

uses tools for surveying the entire genome to assess multigenetic determinants of a drug response

Question 11

gene by environment phenotype definition:

Answer 11

complex interplay between environmental and genetic factors

Question 12

monogenic response v multigenic response:

Answer 12

expression of a single gene yields single phenotype

vs

networks of genes acting together to create a single phenotype

Question 13

recessive trait

Answer 13

phenotype exhibited when a non-functional allele occurs on both the maternal and paternal chromosome

Question 14

dominant trait

Answer 14

phenotype exhibited when a non-functional allele occurs on either the maternal or paternal chromosome

Question 15

co-dominant trait

Answer 15

heterozygotes display an intermediate phenotype as compared to wild type and homozygotes

Question 16

polymorphism definition

Answer 16

variation in the genetic code present at an allele frequency of >=1%

-ex = SNPs

Question 17

single nucleotide polymorphism (SNP)

-genetic consequence:

Answer 17

1) if in coding region:
a) nonsynonymous/missense
- BP change–> single amino acid change (different amino acid!)
- change in protein structure, stability, substrate affinity, intro of stop codon
b) synonymous/sense
- BP change= NO amino acid substitution (still get same amino acid)
- result in dec transcript stability or alter splicing
2) non-coding region:
- promoter
- intron
- reg region
- Results:
- -> transcription factor binding change
- -> enhancer change
- -> splicing change
- -> transcript stability change

Question 18

Indels:

Answer 18

• insteritions = frameshift (change is structure, alter promoter =inc transcript quality, gene dup/mult, stop codon)
• deletions =loss of genetic material (loss of gene; premature stop codon)

Question 19

cosmopolitan polymorphisms:

Answer 19

polymorph common across all ethnic groups

Question 20

population polymorphism:

Answer 20

polymorph that differ between groups (ethnic or race)

Question 21

phenotype to genotype measuring:

Answer 21

drug response outliers are compared to normal responders to identify altered responses to drugs

OUTCOME (PHENOTYPE) AND THEN YOU GO LOOKING FOR WHATS DIFFERENT (GENOTYPE)

Question 22

measure a pharmacogenetic trait:

Answer 22

TRAIT IS NOT THE GENETIC SEQUENCE - ITS THE MEASURABLE RESPONSE TO THE DRUG!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!*** IT IS SOMETHING THAT CAN CHANGE!!!! CANT CHANGE THE GENETIC SEQUENCE SO IT IS NOT A TRAIT!

CAN I CHANGE IT WITH DRUG??=

• enzyme activity
• drug levels in bodily fluids
• drug metabolite in bodily fluids
• physiological response (BP)
• gene expression patterns

Question 23

Adv/Disadv of pharmacogenetic traits:

Answer 23

• adv=sum of all genes giving rise to an effect (LOOKING AT FINAL ENDPOINT)
• disadv=non-genetic influences giving rise to and unstable result (CANT FACTOR DIET OR OTHER DISEASE)

Question 24

Genotype to phenotype definition:

Answer 24

genome is surveyed to determine if genomic variability results in phenotypic variability

Question 25

genotyping:

Answer 25

- testing that reveals the specific genetic sequence of an allele - requires extraction of the DNA from somatic cells (blood or buccal)

Question 26

adv/disadv of genotyping:

Answer 26

1) adv= - DNA is stable - testing needs to be done only once 2) disadv= - dependent upon annealing (TAGGING) of an oligonucleotide sequence to DNA - false pos/neg

Question 27

candidate gene approach:

Answer 27

candiadte gene: - known or partially known cellular pathway involved in a drug response - identify polymorphisms which result in a response (patient screening, data base) - test the polymorphism in a function assay

Question 28

Disadv to candidate gene approarch?

Answer 28

-wrong gene may be studied

Question 29

genome wide approach:

Answer 29

- unbiased survery of the genome | - compare DNA, RNA, or protein of identically treated patients (those with adverse drug reaction vs normal responders)

Question 30

disadv to genome wide approach:

Answer 30

-id of a variation that does not matter

Question 31

Pharmacogenetic phenotype- PHARMACOKINETIC:

Answer 31

- polymorphism in a gene or genes that regulate pharmacokinetics - enzymes or transporters - alter drug concentrations resulting in changes in therapeutic and adverse events P450s, OCT1, CYP2D6, CYP2C9 ... other metabolism enzymes

Question 32

pharmacogenetic phenotype - RECEPTOR/TARGET:

Answer 32

- polymorphism in a gene that codes for drug target - alters drug response (impaired drug binding for example) CHANGE IN DRUG BINDING AFFINITY TO TARGET ex- TYMS, ERalpha

Question 33

pharmacogenetic phenotype- INDIRECT:

Answer 33

-polymorphism in a gene that does not interact with the drug, is not a direct target of the drug, or is not involved with the drugs disposition Ex: APOE, KCNE2

Question 34

Major types of evidence?

Answer 34

- screens of tissue from mult patients linking a polymorphism to a trait - preclinical functional studies - clinical phenotype/genotype studies

Question 35

Results of pharmacogenomic data can lead to:

Answer 35

- id of new drug targets - genomic-specific development of new drugs - genotype-specific dosing regimens