Receptor and other drug targets pharmacogenetics

Question 1

What are the main targets for drug action?

Answer 1

Receptors, Enzymes, Ion channels, Transporters

Question 2

What is typically affected by polymorphisms related to receptors?

Answer 2

Function of receptor or level of expression

Question 3

What is the basic structure of G-coupled protein receptors?

Answer 3

7 transmembrane proteins

Question 4

Which region is important in coupling to G-proteins in G-coupled protein receptors?

Answer 4

Linker region between transmembrane domains 5 and 6

Question 5

Is it usually possible to study phenotype in receptor gene polymorphisms like in CYP genes?

Answer 5

No, it’s not usually possible

Question 6

What methods are used to discover polymorphisms in receptor genes?

Answer 6

Scanning of genes by sequencing or other appropriate methods

Question 7

What are common approaches to study receptor polymorphisms?

Answer 7

• Coding sequence studies
• Upstream polymorphism studies

Question 8

Which receptors are important drug targets related to adrenoreceptors?

Answer 8

Beta 1 and Beta 2 receptors

Question 9

What is the product of the B2-adrenegic receptor gene?

Answer 9

ADRB2 gene

Question 10

How many known polymorphisms are in the coding region of the B2-adrenegic receptor?

Answer 10

9 known polymorphisms

Question 11

What is the first coding region polymorphism identified in the B2-adrenegic receptor?

Answer 11

Arg16Gly

Question 12

What effect does the Arg16Gly polymorphism have on agonist binding?

Answer 12

Gly16 variant enhances down-regulation compared to Arg16

Question 13

What is the effect of the Arg16 form of ADRB2 on short-acting beta agonists?

Answer 13

Associated with increased agonist induced down-regulation

Question 14

Did studies show a difference in response to long-acting beta agonists based on codon 16 genotype?

Answer 14

No, studies failed to show any difference

Question 15

What is the significance of the polymorphism at amino acid 16 in B2 adrenergic receptor?

Answer 15

It is the ligand binding site, outside the cell

Question 16

What haplotypes are associated with B2 adrenergic receptor?

Answer 16

• Ca (Caucasian)
• A (African American)
• As (Asian)
• H-L (Hispanic-Latino)

Question 17

What was the outcome of the study by Connie et al, 2000 regarding B2AR?

Answer 17

Identified 13 SNPs in a continuous region of B2AR

Question 18

What are the main types of adrenoreceptors in the heart?

Answer 18

B1 receptors

Question 19

What is the common polymorphism in the ADRB1 gene?

Answer 19

G389A

Question 20

What is the frequency of the Gly and Arg variants in the ADRB1 gene?

Answer 20

• Glycine variant: 0.26
• Arginine variant: 0.74

Question 21

What is the target enzyme for coumarin anticoagulants including warfarin?

Answer 21

Vitamin-K epoxide reductase (VKOR)

Question 22

What is the gene that encodes VKOR?

Answer 22

VKORC1

Question 23

What percentage of inter-individual variation in coumarin anticoagulant dose do VKORC1 and CYP2C9 account for?

Answer 23

Up to 40%

Question 24

What are the two polymorphisms identified in VKORC1?

Answer 24

• G-1639A
• C1173T

Question 25

What does the presence of the G-1639A polymorphism indicate about VKORC1 expression?

Answer 25

Lower VKORC1 expression

Question 26

What is the common cause of warfarin resistance?

Answer 26

Mutations in the coding region of VKORC1

Question 27

What is the role of HMG-CoA reductase?

Answer 27

Converts HMG-CoA into mevalonic acid, the rate limiting step for cholesterol biosynthesis

Question 28

What is the effect of polymorphisms in the HMGCR gene?

Answer 28

Associated with decreased response to statin treatment

Question 29

What defect is present in cystic fibrosis patients?

Answer 29

Defect in the CFTR gene which codes for an ion channel

Question 30

What drug targets the G551D gating defect in cystic fibrosis?

Answer 30

Ivacaftor

Question 31

What was the improvement in lung function after 48 weeks of Ivacaftor treatment?

Answer 31

Improved by 11%

Question 32

What percentage of cases is D involved in?

Answer 32

Approx. 5% of cases only

Question 33

What is the gating defect in the context of D?

Answer 33

The channel no longer responds to the ligand

Question 34

What drug targets the G551D gating defect?

Answer 34

Ivacaftor

Question 35

What effect does Ivacaftor have on sweat chloride levels after 48 weeks?

Answer 35

Significantly reduced

Question 36

By what percentage did lung function (FEV1.0) improve after Ivacaftor treatment?

Answer 36

11%

Question 37

What is the percentage decrease in pulmonary exacerbations observed with Ivacaftor?

Answer 37

55% decrease

Question 38

What is the cost of Ivacaftor per patient per year?

Answer 38

£150,000

Question 39

For which patients is Ivacaftor approved by the EMA?

Answer 39

Patients over 6 years old with G551D or R117H allele

Question 40

What did a patient quote about the effectiveness of Ivacaftor?

Answer 40

'It's like someone else's lungs are inside of me'

Question 41

What is the target mutation of the drug Orkambi?

Answer 41

Common F508del mutation

Question 42

What two components make up Orkambi?

Answer 42

Ivacaftor plus lumacaftor

Question 43

What does lumacaftor help with in Orkambi?

Answer 43

Movement of CFTR to plasma membrane

Question 44

What is the newest drug that targets F508del more efficiently than Orkambi?

Answer 44

Symkevi

Question 45

What components does Symkevi consist of?

Answer 45

Ivacaftor, tezacaftor, and elexacaftor