Pharmacogenetics and pharmacogenomics

Question 1

What is pharmacogenetics?

Answer 1

Pharmacogenetics is the study of the genetic basis for variation in drug response, often focusing on the large effects of a small number of DNA variants.

Question 2

What is pharmacogenomics?

Answer 2

Pharmacogenomics studies larger numbers of genetic variants, either in an individual or across a population, to explain genetic influences on drug response

Question 3

Who is Archibald Edward Garrod, and what are his contributions?

Answer 3

Archibald Edward Garrod (1857-1936) identified the autosomal recessive inheritance of alkaptonuria and inborn errors of metabolism (1909). He wrote “The Inborn Factors in Disease” (1931).

Question 4

Who is Arno Motulsky, and what did he contribute to pharmacogenetics?

Answer 4

Arno Motulsky (1923-2018) established the Division of Medical Genetics in 1957 and is considered the father of pharmacogenetics. He studied familial hyperlipidemia and earned a Nobel Prize in 1986.

Question 5

What did Werner Kalow contribute to pharmacogenetics?

Answer 5

Werner Kalow (1917-2008) proposed in 1961 that genetic variation in metabolic function could explain individual differences in drug response.

Question 6

What are the factors influencing drug response in patients?

Answer 6

Drug response may be influenced by drug factors, environmental factors, clinical factors, and genetic factors.

Question 7

What is a pharmacogene?

Answer 7

A pharmacogene is a gene that can influence the pharmacokinetics or pharmacodynamics of a drug. Examples include drug-metabolizing enzymes, transport molecules, and drug targets

Question 8

What are the categories of metabolizers in drug metabolism?

Answer 8

Drug metabolism traits can behave in a “monogenic” fashion, resulting in:

Poor metabolizers
Intermediate metabolizers
Normal metabolizers

Question 9

What is the relationship between ethnicity and genetic drug response

Answer 9

CYP3A5 enzymatic activity differs between populations, such as European and African descendants. Ethnic differences can lead to variability in drug response.

Question 10

Give an example of a drug affected by pharmacogenetics.

Answer 10

Codeine is bioactivated to morphine by the enzyme CYP2D6, and variations in CYP2D6 can influence its effectiveness and safety.

Question 11

What is an example of a pharmacodynamic response influenced by genetics?

Answer 11

Malignant hyperthermia is a pharmacodynamic response caused by mutations in RYR1 and CACNL1A3, leading to adverse reactions to anesthetics.

Question 12

What are some well-established pharmacogenes with clinically actionable effects

Answer 12

CYP2C19: Affects efficacy of clopidogrel, omeprazole.
CYP2D6: Affects efficacy of codeine, tamoxifen.
HLA-B: Predicts hypersensitivity to abacavir, carbamazepine.

Question 13

How does genetic variation affect warfarin response?

Answer 13

Inherited variation in CYP2C9, VKORC1, and CYP4F2 influences warfarin’s anticoagulant effect and bleeding risk.

Question 14

What are examples of drugs with differential effects due to genetic factors?

Answer 14

Drugs like rasburicase and antimalarials show differential effects based on G6PD deficiency, leading to adverse drug reactions.

Question 15

What are some pharmacogenomic traits affecting drug response?

Answer 15

Warfarin: Influenced by CYP2C9, VKORC1 variants.
Phenytoin: Affected by CYP2C9 and HLA-B variants

Question 16

What are in silico and in vitro methods for pharmacogenomic discovery?

Answer 16

In silico methods: Use computer-based simulations for drug action.
In vitro systems: Use liver microsomes and cell-based transcriptomics/proteomics to study genetic variants.

Question 17

How can genetic variation be associated with drug action?

Answer 17

Variation can be associated through pseudocholinesterase deficiency, drug level assays, and genome cloning methods.

Question 18

What is the traditional vs. agnostic approach in pharmacogenomic studies?

Answer 18

Traditional approach: Uses clear signals at genome-wide significance to find genetic variants.
Agnostic approach (GWAS): Hypothesis-free method to search for genetic variants affecting common disorders.