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Pharmacogenomics > Week 2 > Flashcards

Week 2 Flashcards

1
Q

What is a reference genome

A

Digital DNA sequence data based as representative of species genome
Not one individual
Often various versions

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2
Q

What does HGVS stand for

A

Human genome varation society

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3
Q

what does g stand for in HGVS

A

genomic

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4
Q

what does c stand for in HGVS

A

coding

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5
Q

what does n stand for in HGVS

A

non coding

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6
Q

what does r stand for in HGVS

A

RNA

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7
Q

what does p stand for in HGVS

A

protein

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8
Q

what does NC stand for in HGVS

A

complete genomic sequence

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9
Q

what does NG stand for in HGVS

A

incomplete genomic sequence

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10
Q

what does NM stand for in HGVS

A

mRNA

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11
Q

what does NP stand for in HGVS

A

protein

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12
Q

explain each part of:

F5NM_000130.3:c1601G>A(p.Arg534Gin)

A 
F5 official gene symbol
 NM is reference sequence
c means coding DNA
 G>A sub at position 1601
 p. means protein Arg to Gln at codon 534
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13
Q

What does number 1 mean in genomic numbering?

A

first nucleotide

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14
Q

what does number 1 mean in coding DNA

A

ATG- start codon of translation

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15
Q

how denotes non coding sequence

A

first half of intron is + then after – from next

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16
Q

deletion annotation

A

c.123delA

_ gives range and write full bases (TATCC)

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17
Q

duplication annotation

A

c.123dupA

_ gives range and write full bases (TATCC)

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18
Q

Insertion annotation

A

Insertion c.123_124insC

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19
Q

indel annotation

A

c.123delinsGTAT

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20
Q

Nonsense annotation

A
  • or Ter
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21
Q

What does star allele nomeclature identify

A

CYP3A5*2 identifies genetic variant need to go onto database to look at

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22
Q

Rule 1 of star allele

A

if letter after number then gives other variants that don’t have an effect

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23
Q

Rule 2 of star allele

A

if variant identifies splice variant ad others travel other variants travel with that may have an effect but not as strong an effect- less relevant

24
Q

problems with star allele

A

Interpretations should be consistent- not all genes have committees
Need to be maintained on ref tables
Some Pgx genes use more than 1 nomenclature systems
variation

25
Q

What is an rs number

A

Reference SNP cluster ID specific number for SNPS

26
Q

international workgroup reccomendations (see if this is actually improtant)

A

Use HGNC to specify
Report using HGVS
Report rs IDs
Use haplotype translation tables to convert * alleles
Indicate each variant observed
List of variations can be detected with a test
Describe test including limitations
Test description should be publicly available

27
Q

UCSC annotation

A

hg

28
Q

genome reference consortium annotation

A

CRCh

29
Q

What is a trasncript

A

Single gene can be transcribed to multiple RNA single gDNA cahnge can result in different cDNAs

30
Q

What enzyme metabolises codeine and where does this occur

A

CYP2D6 in the liver this is highly polymorphic with over 100*

31
Q

ultra rapid codeine metabolisers, activity score frequency and guidelines

A

> 2- more than 2 copies of functional- avoid- 1-2%

32
Q

Normal codeine metabolisers, activity score, frequency and guidelines

A

1-2-two alleles for full or reduced function – use label recommended age or weight on label (77%-92% of individuals)

33
Q

Intermediate codeine metabolisers, activity score, frequency and guidelines

A

0.5 one reduced function and one non functional - use label recommended age or weight on label if don’t react then possibly change 2-11%

34
Q

codeine metabolisers, activity score frequency and guidelines

A

0- no functional alleles avoid (5-10%)

35
Q

Phase 1 reactions and product

A

oxidation reduction and hydrolysis

36
Q

Phase 1 effect on active drug

A

Either inactivate active drug- metabolites inactive or metabolites less active than original drug

37
Q

Phase 1 effect on pharmacologically inactive drug

A

one of metabolites is active - prodrug

38
Q

Cytochrome P450

A

monooxygenases- use heam to oxidise molecules often making more water soluble for clearance by adding or unmasking polar group

39
Q

Hydroxylation mechanism

A

hydrogen on drug hydroxylated to Ok group

40
Q

What does hydroxylation do

A

small increase in hydrophilicity exposing functional group

41
Q

Phase II effect

A

changes Phase I metabolite into compound soluble enough for excretion

42
Q

conjugation

A

large increase in hydrophilicity, polar compound added to functional group, facilitates excretion

43
Q

action of opiods

A

Decreased AC activity so decreased cAMP

Binding to opioid receptor block CA channels in presynaptic so ca doesn’t enter so less synaptic vesicles released

Binding of opioid to post synaptic causes more K to be released so more inhibition of synaptic vesicles from presynaptic side
Overall reduced neuronal release

44
Q

action of Tramadol

A

Some activity at Mu-opiod receptor and inhibits synaptic reuptake of serotonin and norepinephrine inhibit pain transmission at spinal cord

45
Q

activity of tramadol pre and post metabolism

A

Active drug but Metabolism- one main metabolite M1 tramadol contributes significantly higher than tramadol

46
Q

enzymes invovled in tramadol metabolism

A

CYP2D6 catalyzes production of M1

CYP2B6 and CYP3A4 catalyse M2 which is inactive

47
Q

Tramadol guidelines

A

CYP2D6 poor metabolizers often don’t have as much analgesia and ultra rapid could have a lot more but no individual CPIC guidelines

48
Q

Thiopurine use

A

Used for treatment of inflame, autoimmune, leukaemia and to prevent rejection

49
Q

TPMTs

A

Thiopurine methyl transferases (TPMT methylate’s thipures to inactive non-toxic form in phase II metabolism

50
Q

side effects of thipurines

A

neutropenia- bone marrow suppression, hepatotoxicity, nausea and comiting and pancreatities

51
Q

frequency fo variation for thiopurines

A

89% have normal TPMT enzyme actvicty
11% low TPMT
0.3% have undetectable levels

52
Q

testing different levels of TPMT activity

A

1- conventional dosagesgiven to all apteitns
Higher cellulr contc of active thioguanine nucleotides in TPMY deficient- more toxicity
2- genotype specific dosing
Similar thiopurines levels achieve, less toxicity
Show by indivdiaulising dose can get therapeutic effect

53
Q

Thiopurine FDA guidelines

A

genotyping
1/1 standard
Heterozygous for low 30-70% standard
Homozygous for low activity- consider alternative medication or 10% of standard dose

54
Q

UK guidelines for thiopurines

A

10% of pop have low- measure TPMT activity prior to start and if undetectable generally not treated an with low then receive reduced dose

55
Q

when is genotyping done for thiopurines in UK

A

deficient TPMT or previous sever reaction or blood transfusion

56
Q

issue with testing enzyme activity

A

can miss if blood transfusion

Pharmacogenomics (11 decks)

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