Polymorphisms from every lecture

Question 1

UGT1A1 poly

Answer 1

*28, 7 (TA) instead of 6

Question 2

UGT1A1 substrate

Answer 2

SN-38

Question 3

TMPT polymorphisms

Answer 3

TPMT*1 = WT

TPMT*2 = G–>C

TPMT*3A = G–>C A–>G

TPMT*3C = A–>G

Question 4

TPMT substrate

Answer 4

6-mercaptopurine

Question 5

Decreased activity DPYD polys

Answer 5

A –> T
G –> A

Question 6

Loss of function DPYD poly

Answer 6

*2A - skipping of exon 14

Question 7

DPYD substrate

Answer 7

5-fluorouracil

Question 8

Decreased activity CYP2C9 polys

Answer 8

*2 Arg144Cys
*3 Ile359Leu
missense mutations

Question 9

CYP2C9 substrate

Answer 9

Warfarin

Question 10

Decreased activity CYP2C19 polys

Answer 10

*2 G681A
*3 G636A

Question 11

Increased activity CYP2C19 poly

Answer 11

*17 - upstream, increases activity

Question 12

CYP2C19 substrate

Answer 12

Cyclophosphamide
Omeprazole
Diazepam
Clopidogrel

Question 13

NAT2 polys

Answer 13

*4 WT

*5 C–>T

*6 G –> A

*7 G –> A

Question 14

NAT2 substrate

Answer 14

Isoniazid

Question 15

SULT1A1 polys

Answer 15

Copy number variations

3’ UTR T allele (C–>T) increased miRNA binding –> decreased expression of gene

Question 16

SULT1A1 substrates

Answer 16

Tamoxifen
Paracetamol

Question 17

No activity CYP2D6 polys

Answer 17

*3 frameshift

*4 splicing defect/exon 4 skipped

*5 gene deleted

Question 18

Increased activity CYP2D6 poly

Answer 18

Ultra-rapid metabolisers have extra copies

Question 19

CYP2D6 substrates

Answer 19

Codeine
Antidepressants
Antipsychotics
Beta-blockers

Question 20

What is VKORC1

Answer 20

encodes vitamin K epoxide reductase

Question 21

VKORC1 poly and clinical consequence

Answer 21

G –> A decreased activity
Less enzyme made
More sensitive to Warfarin
Lower dose needed

Question 22

HLA-B polys and clinical consequence

Answer 22

*57:01 = abacavir hypersensitivity

*15:02 = stevens-johnson syndrome and toxic epidermal necrolysis from carbamezapine

Question 23

B1-AR poly and consequence

Answer 23

Arg –> Gly = increased G protein interaction & increased adenyl cyclase

Question 24

B1-AR substrate

Answer 24

Beta blockers (metoprolol)

Question 25

B2-AR poly and consequence (2)

Answer 25

on exon 6 (outside of cell so G coupling not affected) Ile 164 variant is rare but causes decreased receptor signaling, worse heart failure and impaired exercise capacity - worse response to salbutamol

Question 26

a2-AR poly and consequence

Answer 26

G-->C G: increase peripheral vascular resistance C: decreased hypotensive response

Question 27

CYP3A4 polys

Answer 27

*1B decreased - upstream *2 Ser222Pro *22 decreased intronic -->T

Question 28

CYP3A4 substrates

Answer 28

Cyclosporin Steroids

Question 29

CYP2A6 polys

Answer 29

*2 Leu --> His *4 whole gene deletion *5 Gly --> Val

Question 30

CFTR polys and substrate

Answer 30

/_\f508 : protein not located in membrane G551D: protein correctly located but channel doesn't transport Cl- (gating defect) Ivacaftor - improves channel opening (improve lung function) in people with gating defect but useless for f508 poly

Question 31

SLCO1B1 poly and clinical consequence

Answer 31

Val --> Ala decreased transporter activity Homozygous carriers of the poly can have over twice the exposure to active simvastatin - increases risk of statin-induced myopathy

Question 32

ABCB1 polys

Answer 32

On exon 12, 21 and 26 all results in T haplotype 12 --> alters expression & affects drug pharmacokinetics 21 --> alters function & improves response to taxanes 26 --> alters expression & increased drug toxicity (neurotoxicity) & increase cancer risk

Question 33

G6PDH deficiency

Answer 33

Needed for GSH production for protection against oxidative stress Genetic defect on X chromosome Exposure to sulphamethoxazole may trigger haemolytic anaemia

Question 34

PON1 polymorphism

Answer 34

Q192R Arg-->Gln

Question 35

PON1 substrates

Answer 35

Organophosphates Higher Diazoxon metab Lower Paraoxon metab

Question 36

ALDH poly

Answer 36

ALDH2 Glu-->Lys

Question 37

FMO poly & consequence

Answer 37

E158K/E308G quite common Decreased activity Fish odour syndrome

Question 38

FMO substrates

Answer 38

TMA Sulindac (NSAID in chemoprevention - prodrug activated by gut flora, better outcome in people with polymorphism)

Question 39

Which CES have they found poly in

Answer 39

CES1 Gly --> Glu (low)

Question 40

COMT poly

Answer 40

G-->A lower activity

Question 41

COMT substrate

Answer 41

catecholamine metabolism noradrenaline --> normetanephrine