Receptor and other drug target pharmacogenetics Flashcards by libby blencoe

what is the difference between polymorphisms in receptor and in metabolic proteins

you don’t see complete absence of the protein in receptors

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what is the two ways that polymorphism can affect G-protein linked receptors

Either the receptor or the coupling process of the G-protein

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How are polymorphism studied compared to metabolic

Not able to study phenotype in same way as metabolic
scanning genes by sequencing
can use knock out mice (maybe?)

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How is coding sequences used to study polymorphisms

Express variant in suitable cell line and compare function (response to
agonist or antagonist) with wild-type

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How are upstream polymorphism used to study polymorphisms

reporter genes (luciferase) are place in a promoter region and then placed in a vector and transfected into cell line
can use alkaline phosphatase (less sensitive, No need to lyse cell as product in released into medium)

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What is B2-adrenergic receptor

-product of introless gene with coding region of 1239bp

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what are the polymorphisms in the coding region of with B2-adrenergic receptors

9 known polymorphisms, resulting with 4 amino acid substitutions
Arg16Gly
Gln27Glu
Val34Met
Thr164Ile

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what is the polymorphism in the leader peptide of B2-adrenergic receptor

Arg19Cys

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how many upstream polymorphism are associated with B2-adrenergic receptor

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what is a haplotype

combination of alleles on a
particular chromosome. Often will get linkage
with some polymorphisms occurring together

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What are the 3 common haplotypes of B2-adrenergic receptor in Europeans

2,4 & 6

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What haplotypes of B2-adrenergic receptor are seen in African americans

1 is also common as well as 4 and 6
2 is rare

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What haplotype of B2 adrenergic receptor has the smallest change in FEV when B agonist is administered

4/4
both AA at 16 is arginine

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What haplotype of B2 adrenergic receptor has the largest change in FEV when B agonist is adminstered

4/6
One AA at 16 is arginine and one is glycine

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which haplotype of B2-adrenergic receptor responed better to placebo than to salbutamol

4 - Arg

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where are B1 receptors mainly located and what are the main type of drugs associated

in the adrenoreceptor in the heart
b blockers = Atenolol

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what is the main polymorphism associated with B1 adrenoreceptors and what is the frequency of theses variants

Gly389Arg amino acid
Gly variant has frequency of 0.26, Arg 0.74

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what is the effect of Gly389Arg polymorphism in B1-adrenorecptors

Arg form shows enhanced Gs protein interaction and increased adenyl
cyclase activation

what is the pharmacological effect B1 adrenergic receptor polymorphims

Patients homozygous for the Arg have a better response to metoprolol

what is the gene for the enzyme for coumarin anticoagulants (warfarin)

VKORC1

what is the protein which is the target for warfarin

Vitamin K epoxide reductase

True/False - There should be no difference between patients in the dosing of warfarin to achieve good clotting

False - individuals have varying doses
there are also some patients who are warfarin resistant

what is the normal dose of warfarin

5 mg/day
each patients should be titrated to measure clotting though

what is the vitamin K cycle

-Vitamin K is needed as a cofactor for carboxylase enzyme - the process to make the clotting factors then generates vitamin K epoxide - this must be regenerated to Vit K by VKOR

what is the two polymorphisms in VKORC1

G1639A - in upstream region C1173T - in the first intron

how many exons are in VKORC1 and how

True or false -Polymorphisms in VKORC1 are inherited independently

False, due to small size, two polymorphism are almost always inherited together

G-1639A and C1173T form part of haplotype associated with __ warfarin dose

lower

which VKORC1 haplotype has higher expression of VKOR

Homologous for wildtype

In the overall population, what is most people's genotype (VKORC1)

Heterozygous

what is the only group of people who can take more than 8mg warfarin per day

homozygous for wildtype

what is warfarin resistance

patients doesn't respond to W or needs unusually high dose (>10mg/day) - Normally its due to non-compliance - some patients have mutations in coding region of VKORC1 - affects W binding but not Vit K epoxide reduction

True or false - due to few mutation which could cause pharmacodynamic warfarin resistance, population frequency is very low

False There are several mutation This means screening prior to treatment is not considered due to rarity

What is the mutation which is more common in Isreal, Egypt and Ethiopia which can cause warfarin resistance

D36Y

What are the two genes which effects warfarin dose

CYP2C9 & VKORC1

Which of the two genotypes relating to Warfarin dose, causes a patient to require the highest dose

Wildtype - CYP2C9 Wildtype - VKORC1

Effects of VKORC1 genotype affecting warfarin dose is seen less in subjects with CYP2C9(*2/*3) or CYP2C9(*3/*3) why ?

There are less people who have these genotypes therefore less variation

All cystic fibrosis patients have defect in __ gene which codes for __ involved in __ transport

CFTR ion channel Cl-

what is the most common genetic defects involved in Cystic fibrosis

F508 (single amino acid [phenylalanine] deleted) so the protein is not inserted into the cell membrane

5% of patients have this genetic polymorphism which causes the channel to reach the cell surface but not transport Cl-

G551D - channel no longer responds to ligand

what is the cellular effect of the Cystic fibrosis polymorphism Class 3 (G551D)

missense mutation results of AA substitution which disrupts regulation of teh CRFT channel

which drug reverses the G551D mutation in CRFT channel

Ivacaftor