Pharmacogenetics

Question 1

Pharmacogenetic vs. pharmacogenomics

Answer 1

Genetic basis for variation in drug response include genomics which surveys the genome entirely to asses genetic diversity

Question 2

6-mercaptopurine example

Answer 2

Treats childhood acute lymphoblastic leukemia. 1 in 100 children have a variant thiopurine methyltransferase, which prevents 6-MP metabolism drug accumulates to fatal result. Now all children are screened before 6-MP administration

Question 3

Poor metabolizers of Clopidogrel example

Answer 3

Anticoagulant, variant CYP2C19 with poor activity results in low active species in plasma. Treatment failure. test for poor metabolism - probe substrate or genetic screen.

Question 4

Phenotype to Genotype

Answer 4

Evaluate drug metabolizer outliers and determine genetic polymorphisms. Historical method

Question 5

Genotype to Phenotype

Answer 5

Scan genome, identify polymorphisms, determine if they translate to phenotypic activity

Question 6

Monogenic trait example

Answer 6

CYP2D6 poor metabolizer

Question 7

Multigenic traits

Answer 7

harder to predict phenotype, and a continuum of phenotypes are present - classic dominance patterns breakdown

Question 8

Polymorphisms

Answer 8

variation in DNA sequence that is present in 1% or greater in the population. SNP, Insertions/Deletions, and Copy number variation

Question 9

cSNP

Answer 9

coding SNP: Missense (non-synonymous) - amino acid change. Sense (synonymous) - no amino acid change (can still change phenotype). Nonsense - early stop codon

Question 10

SNP in non-coding region

Answer 10

Can result in translatability, stability, splicing, DNA tertiary structure and replication

Question 11

Haplotype

Answer 11

Set of SNP on single chromosome that is statistically associated.

Question 12

Linkage

Answer 12

Equilibrium - independent, disequilibrium - not independent, complete disequilibrium - genotype at 2 loci always occur together

Question 13

NAT2 example

Answer 13

Catalyzes N-acetylation of a large number of drugs (procainamide, caffeine, etc.) Considerable ethnic variation. Slow acetylators - increased risk of polyneuropathy with isoniazid, increase risk of bladder cancer, hemolytic anemia with sulfa drugs. Fast acetylators need more drug for therapeutic effect. Fast activity is dominant

Question 14

Alcohol Dehydrogenase

Answer 14

ADH2 variant convert alcohol to down stream substrates faster leading to flushing with alcohol consumption.