Pharmacogenomics

Question 1

Allele

Answer 1

Original or variant form of a gene at a particular location on a chromosome.

Question 2

Genotype

Answer 2

The genetic makeup of an organism or cell, the 2 specific alleles inherited for a specific gene.

Question 3

Haplotype

Answer 3

Combination of alleles closely linked in a single chromosome that are inherited together

Question 4

Nucleotide

Answer 4

Structural unit of DNA. Contains sugar moiety, phosphate group and a base

Question 5

Pharmacogenetics

Answer 5

The study of genetic causes of individual variations in drug response.

Question 6

Pharmacogenomics

Answer 6

The genome-wide analysis of genetic determinants of drug efficacy and toxicity.

Question 7

Phenotype

Answer 7

The physical characteristics of the genotype

Question 8

Polymorphism

Answer 8

Variation in the DNA sequence that is present in > 1% of the population

Question 9

SNP

Answer 9

A type of polymorphism involving 1 single base

Question 10

Poor metabolizer

Answer 10

Phenotype/genotype of an individual who possesses a low (poor) rate of metabolism

Question 11

Ultra-rapid metabolizer

Answer 11

Phenotype/genotype of an individual who possesses a very high rate of metabolism

Question 12

Explain the nomenclature of SNP naming systems (Numeric and alphabetic, star, and genotype)

Answer 12

ABCB1 3435 C>T
1. First few letters correspond to specific gene
2. The numbers 3435 determine the location on the chromosome
3. C represents the original or reference nucleotide and the T represents the variation (A T is in place of the C)
Star represents the allele subtype
CYP2C9*1= normal (wild type) enzyme activity
2/2=homozygous
2/3=heterozygous
1/2 or 1/3=reduced enzyme activity
2/3 or 3/3= no enzyme activity

Question 13

Explain the hypersensitivity reaction seen with abacavir

Answer 13

Patients who are HLA-B5701 positive can develop a life-threatening hypersensitivity reaction to abacavir if they take it. Patients must be HLA-B5701 negative before initiating treatment with abacavir. Rechallenge should never occur.

Question 14

Explain the genetic basis for underlying poor and ultra-rapid metabolizers of CYP2D6

Answer 14

Poor metabolizers have 2 copies of inactive 2D6 alleles and thus little to no enzyme activity.
Ultra-rapid metabolizers have more than 2 copies of active 2D6 alleles.
We know what effect this will have on all the PK parameters.

Question 15

Discuss the recommendations for genotyping for 2D6 in patients taking SSRIs

Answer 15

Insufficient evidence exists to support recommending for or against genotype testing before initiating SSRIs metabolized by 2D6.

Question 16

CYP2C9 and VKORC1 may influence the metabolism of which medication

Answer 16

Warfarin
2C91 indicates normal (wild type) enzyme function
2C92 or 3 have decreased enzyme activity by 50-90% thus putting the patient at increased risk for bleeding. You should give this patient a lower dose of warfarin because they will have higher plasma concentrations compared to those who metabolize the drug normally (2C91)

Question 17

Discuss the recommendations and role of genotype testing in warfarin therapy

Answer 17

Testing is not required and health professionals should not delay therapy for genetic testing. Not appropriate for patients already on warfarin. The CMS decided to cover pharmacogenomic testing to Medicare beneficiaries who: Have not previously been tested, have received < 5 days of therapy AND are enrolled in clinical study that meets high standards

Question 18

Which polymorphisms are detected by the Rapid Genotyping Assay

Answer 18

CYP2C9 and VKORC1 for warfarin

Question 19

Why is CYP2C19 genotyping recommended for patients who are moderate-high risk for cardiovascular events who are treated with clopidogrel

Answer 19

Plavix is a prodrug that required CYP2C19 metabolism in order to cardioprotective effects (anti platelet). In 2010, FDA issued BBW stating that patients with 2C19 polymorphism may require higher doses or a different medication altogether with.

Question 20

Explain how genetic variation in HER2 expression and EGFR sensitivity influences response to antineoplastic therapy

Answer 20

HER2 overexpression indicates poor prognosis in breast cancer. However, trustuzumab has been successful in patients who are HER2 positive.
Increased sensitivity to EGFR is a good thing because the therapy that targets EGFR is extremely successful.

Question 21

Discuss the feasibility, ethical, legal and economical issues that impact incorporation of genomics into clinical practice

Answer 21

It is expensive and not widely practiced.