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Pharmacogenomics Flashcards

1
Q

What is a haplotype?

A

An inheritable, proximal block of SNPs on the same chromosomes

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2
Q

Example of SNP variation

A

TAS2R38 gene variation and PTC taste

  • Mendelian Inheritance pattern
  • 3 Phenotypes; Super-taster, taster, non-taster
  • As an inheritance pattern, has been inherited after species divergence
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3
Q

TD50

A

Dose at which toxicity occurs in 50% of cases

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4
Q

ED50

A

Dose at which the drug is effective in 50% cases

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5
Q

G6PD Deficiency: what it is

A
  • Glucose 6 Phosphate Dehydrogenase- enzyme that metabolises glycosides
  • G6PD deficiency is an X-linked recessive disorder with 140 single-base changes
  • 5 classes of enzymatic variation
  • 400 million affected worldwide, most common Sub-Saharan africa
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6
Q

How is G6PD deficiency diagnosed

A

Quantitative spectrophotometric analysis

Flow cytometric assay (assesses RBC G6PD activity)

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7
Q

Classes of enzymatic variation in G6PD deficiency

A

Classes 1-5
Class I- severe, deficient haemolytic anaemia
Class IV- normal activity
Class V- increased activity

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8
Q

G6PD deficiency in Malaria

A

G6PD creates NADPH which removes oxidants, such as those generated by antimalarials

  • Primaquine (antimalarial treatment) produces excess oxidants, which can’t be removed by NADPH supply
  • Destroys RBC membranes and causes haemolytic anaemia
  • Sx: Acute haemolysis, jaundice, tiredness, SOB, dark urine
  • CI in pregnancy
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9
Q

Other drugs CI in G6PD deficiency

A

Sulfasalazine

Nitrofurantoin

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10
Q

Isoniazid- what for, features etc.

A

Nicotinic acid derivative used in TB treatment

  • Blocks mycolic acid synthesis (component of the mycobacterial cell wall)
  • Metabolised to its active form by N-Acetyltransferase 2
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11
Q

NAT-2 Variation

A

3 SNPs in NAT2 gene; two are synonymous

  • Species and geographical variation
  • Rapid, intermediate and slow acetylators
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12
Q

Symptoms of slow acetylators with Isoniazid

A

Peripheral neuropathy, hepatotoxicity, neuritis

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13
Q

Meta-analysis of acetylator studies:

A
  • NAT2 variation accounts for 88% variability of isoniazid metabolism
  • Rapid acetylators have higher rates of microbiological failure, particularly for combination therapy
  • ADRs also more common
  • Genotype/phenotype disconcordancy in 5% patients
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14
Q

Further PK issues with TB treatment

A

Isoniazid and Rifampicin both first-line

Variation in Rifampicin activity may also be associated with SNPs of SLCO1B1

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15
Q

How was CYP2D6 variation established

A

Variation in Sparteine activity with increased effects in 7% mothers (induces uterine contractions)
- Sparteine is metabolised by CYP450 into Sparteine-N1-Oxide, then into 2 inactive metabolites

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16
Q

CYP2D6 variation

A

CYP2D6 metabolises 25% of clinically-used drugs, importantly Theophylline, COCP, Warfarin, Carbamazepine, and Phenytoin

  • Phenotypes: Ultrarapid (UM), Extensive (EM), Intermediate (IM), Poor (PM)
  • EM most common in caucasians
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17
Q

Effects of codeine and CYP2D6 status

A

O-methylation of codeine to morphine is essential for its analgesic activity, but only 10% metabolism

-ADRs are more common in UMs e.g. respiratory depression, with standard PO 25mg TDS in one patient

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18
Q

Clinical study of variation of Codeine and CYP2D6

A

EMs vs PMs (single PO 75mg codeine dose)

  • Increased pain thresholds to nociceptive laser stimuli
  • Reduced urine codeine concentration
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19
Q

Clinical study of variation of Tramadol and CYP2D6

A

AUC (blood-drug concentration) is lower for both enantiomers of Tramadol in PMs vs EMs

  • Pain Pressure
  • Nociceptive reflex
  • Cold pressor reflexes

Have different responses in PMs and EMs
-PMs only had significant response to pressure-pain tolerance and nociceptive reflex

SEs: nausea, dizziness, tiredness

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20
Q

Opioid toxicity in neonates/mothers

A

-Neonates breastfeeding from UM mother died (concentration in breastmilk was too high; neonates have impaired morphine mwtabolising/eliminating capacity)

  • Opioid exposed newborns may have greater methylation of the CYP2D6 gene and related genes- reduced expression, lower metabolism
  • In a methadone maintained model of opioid dependent mothers
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21
Q

Epidemiology of Bipolar Disorder

A

Significant cause of global morbidity (QALYs)
Increased mortality vs. non-bipolar patients
-Suicide increased (but lower than unipolar depression)
-Medical deaths increased

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22
Q

Bipolar I

A

Manic and depressive episodes

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23
Q

Bipolar II

A

Hypomaniac and depressive episodes

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24
Q

Cyclothymic disorder

A

2 years of hypomaniac periods

Bipolar NOS- other medical conditions causing a mood disorder

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25
Symptomatic features of Bipolar
Mania Hypomania Depression Subsyndromal Depression
26
Features of Mania
Extreme happiness w/euphoria, grandiosity, impulsivity, libido, social intrusiveness - Psychotic Sx (delusions, hallucinations, formal though disorders) - Cognitive Sx (racing thoughts, distractibility, disorganisation, in-attentiveness)
27
Treatments for Bipolar
Mania - Antipsychotics (Haloperidol, Risperidone, Olanzapine) - Lithium +/ Sodium valproate if first line ineffective Long Term management -APs OR Lithium +/ Sodium Valproate
28
Lithium treatment in Bipolar
The most-prescribed drug Requires monitoring Exerts clinical effects by inhibition of Inositol Monophosphatase, Glycogen Synthase Kinase 3B, and Adenylyl Cyclase Response to lithium may be a familial trait which clusters in families - Twin studies have shown lithium prophylaxis is better in twins whose co-twin also has BPD
29
Purpose of Genome wide association studies
Identifying loci that increase disease risk and predict treatment response
30
GWAS of Chinese individuals and lithium response Chen 2014
High specificity/sensitivity (linkage disequilibrium) for 2 SNPs in Glutamic Acid Decarboxylase Like 1 Enzyme (GADL1) on Chr3 - Inclusion criteria: clinical course, adherence, minimising the influence of other medications - Patients with SNPs and rapid disease cycling had a better treatment response -GADL1 similar to GAD65/67, underexpressed in bipolar patients
31
Follow up Chen 2016 study (bipolar)
Carriers of T allele have lower frequencies of recurrent affective episodes than non-T carriers during period adherence -One GADL1 SNP and medication adherence contribute to treatment response
32
Additional GWAS study for lithium response Squassina 2011:
GWAS of 200+ Sardinian patients - GWAS and Quantitative trait analysis - SNP in intron 1 of the ACCN1 gene - Encodes a cation channel with high lithium permeability and Na+ affinity
33
Genetic variants and lithium response GWAS
4 SNPs on Chr21 on long non-coding RNA genes - Strong linkage disequilibrium to lithium response - lncRNAs are important regulators of gene expression in the CNS and may decrease during manic episodes
34
Evidence against GADL1 involvement in lithium variation Birnbaum 2014
Microarray/ RNA sequencing identified minimal GADL1 expression throughout the brain Autopsies identified minimal GADL1 protein expression Western blot of mouse brain lysates shows that this reduces with age
35
Role of GADL1 in the Kidney
Is abundantly expressed and involved in PLP-dependent taurine synthesis Taurine may cross the BBB to interact with glutamate NMDA receptors -Relation to GADL1 in bipolar
36
Switching in Bipolar
The sudden transition from one mood polarity to the other PM CYP2D6 patients likely to experience switching more frequently after introducing a new drug Pharmacogenetic testing relevant e.g. Amplichip CYP450 test
37
Features of lung cancer
Non-Small Cell most common (75%) 50% cases inoperable so cytotoxic chemotherapy is first line treatment - SEs of chemo: Nausea, vomiting, myelosuppression, alopecia, impotence, teratogenicity, carcinogenicity -17% 5 year survival
38
EGFR pathway in NSCLC
15% of the 55% of NSCLC patients with mutations have an EGFR mutation Increase protein expression/phosphorylation in EGFR-dependent pathways which increase Ras/Raf, PI3K/AKT pathway activation - Induce proliferation and angiogenesis
39
EGFR mutations
Normally in the kinase domain Increase sensitivity to TK inhibitors (Gefitinib, Erlotinib) L858R mutation: increases Gefitinib sensitivity T790M mutation acquired resistance to TK inhibitors
40
Benefits of Gefinitib treatment in L858R/ Exon 19 NSCLC patients
Improved clinical outcomes In vitro: 50x sensitivity to Gefitinib treatment
41
HER2 and breast cancer
HER2 o/e in 20% breast adenocarcinomas | Mutation is associated with worse untreated prognosis
42
Phase 2 RCT of Trastuzumab with HER o/e breast cancer Vogel 2002 Phase 3 RCT
114 women with o/e identified by IHC, FISH Trastuzumab administered at 2 doses Clinical benefit demonstrated showing no disease progression at 12 months vs. controls P3 RCT: effectively enhanced first-line chemotherapy
43
EGFR in Gastric/GOJ cancers Bang 2010 P3 RCT
Multi-centre P3 RCT to account for ethnic differences Inclusion based upon IHC/FISH Improved overall and progression-free survival when used adjunctively to chemotherapy - No effect upon number/magnitude of ADRs
44
Effects of BCHE mutations on Succinylcholine/ Mivacurium activity Gatke 2007
Mutations responsible for variation in BChE prolong drug activity BCHE*FS126- produces a truncated protein lacking an active site BCHE*328D- produces an inactive protein due to a radical AA change Have extensively prolonged succinylcholine activity- prolonging respiratory depression and apnoeas May also have sever reactions to Donepezil etc.
45
Jensen 1995- determining genetic variation in Succinylcholine activity
Used differential inhibitors of BCHE - There were no age/sex differences under 10 years - Activity decreased with age
46
ALOX5 status and Asthma
ALOX5 encodes 5-Lipooxygenase (5LPO)- involved in leukotreine/ Arachidonic acid synthesis 5LPO encoded by ALOX5 gene; has a variable number of tandem repeats (VNTRs) in promoter region -Only fully expressed with 5VNTRs Cells with more/less VNTRs less active in vitro Patients with mutant ALOX5 have a poorer response to Zileuton (5-LPO inhibitor used in asthma) by FEV1 score
47
What does the clinical pharmacogenetics implementation consortium (CPIC) do?
Create gene/drug practice guidelines for implementation of certain drugs
48
Variation in TMPT activity and Thiopurine drugs What are the alleles- and effects?
Thiopurines e.g. 6-MP are purine analogues, prevent DNA formation Have a narrow TI, increased risk of myelosuppression 3 alleles of activity: - TPMT1: 90%, high activity - TPMT*3A: 10%, intermediate activity - TPMT*3C: 0.3%, low activity- increased risk of myelosuppression (6MP levels remain higher for longer)
49
Why are the effects seen in 3A/3C allele patients
The protein encoded by 3A/3C is degraded rapidly by a ubiquitin-proteasome mediated process Naturally higher in neonatal RBCs vs age-matched adults
50
ALL and TPMT activity
Children with ALL have better outcomes if they also have low TPMT activity - Higher concentrations of TGN metabolites can form from lower doses - Allows dose lowering in deficient patients, so chemo can be delivered at maximum doses - Reduced rates of mercaptopurine-induced neutropenias
51
Clinical implementations of thiopurine dosing
Genotyping, phenotyping (radiochemical, chromatographic techniques) - Concordance of ~86% - Can be influenced by RBC transfusion 3A individuals need to be treated with 1/10 of standard dose High activity may need elevated dose Genotyping is worth it- the cost of 400 genotyping tests is the same as 1 treatment of a TPMT associated ADR
52
Warfarin administration
Inhibits Vitamin K Epoxide Reductase (VKOR) to reduce clotting cascade activation Is administered as R-Warfarin but the more potent S-Warfarin is inactivated by CYP2C9
53
Variation in warfarin activity- CYP2C9 and VKORC1
CYP2C9- 9% of variability - *1 allele is highest activity - *2 allele reduced activity - *3 allele is minimal/no activity VKORC1- 25% variability - G allele- high liver expression - A allele- low liver expression May also have complete loss of function mutations
54
Warfarin Dosing Refinement Collaboration
Genotype-specific warfarin dosing | -2014 meta analysis suggests this does not reduce dosing-related ADRs
55
Other clinical considerations in warfarin dosing
Maintain an INR of 2-3 May be affected by other AC use Interactions with other CYP450 drugs may occur
56
Inhibitors of CYP450
Grapefruit/Cranberry juice, valproate, miconazole, Erythromycin, Ciprofloxacin
57
Inducers of CYP450
Carbamazepine, Phenytoin, Rifampicin, Alcohol, BBQ meat, St Johns Wort
58
Indications of Carbamazepine
Focused/ Generalised Tonic/Clonic Seizures | Trigeminal Neuralgia
59
Side effects of CBZ
Anaemias and blood disorders Ataxia Dizziness, blurred vision, Nausea
60
Mechanism of action of CBZ, and how metabolised
Blocks voltage-gated Na channels in neurons | Metabolised by CYP3A4
61
What effects might CBZ have on CYP3A4
Induces it- may affect transcription/+ expression of CYP3A4/5 via the Pregnane X receptor
62
Effects of CYP3A4 genotype of CBZ Korean epileptics study
35 Korean epileptic patients Investigate CYP3A5*3 expression effects CYP3A4 activity may vary 20x in vivo Positive correlation between dose-requirement and serum level of CBZ in expressors and non-expressors Oral clearance of CBZ in non-expressors was significantly lower and therefore serum levels were significantly higher
63
Carbamazepine and SCN1A
SCN1A- encodes VG Sodium channels in neurons SNP7 of the SCN1A gene highly associated with maximum dose Less of an issue with CBZ than with phenytoin Starting doses are normally less than the final req.d dose 400mg OD vs 800-1200mg OD

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