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Genetics 2017 > 14. Pharmacogenomics and nutrigenomics (wk11) > Flashcards

14. Pharmacogenomics and nutrigenomics (wk11) Flashcards

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1
Q

2 main goals of pharmacogenomics

A

1) Search for new drugs and drug targets

2) Influence of genetic variations on drug response in patients

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2
Q

Protein coding genes vs drug targets

A

400 drug targets
20 000 protein coding genes (and RNA etc)
At least 10x more drug targets than today

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3
Q

Drug response pharmacogenomics

A

1) Some drugs against diseases are ineffective in certain people
- 30%: beta-blockers in HT, 50 % antidepressants
- Normal- vs altered- vs no response

2) Adverse drug response
- Normal- vs cationary- vs toxic response
* Cause 60-80 % genetic differences between individuals

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4
Q

Pharmacodynamics

A

What the drug does to the body

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5
Q

Pharmacokinetics

A 
What the body does to the drug
ADME:
- A: absorption
- D: distribution
- M: metabolism
- E: elimination
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6
Q

Pharmacogenomics

A

How genetic variations in the pharmacokinetic and pharmacodynamic processes influence the effect and side effect of the drugs

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7
Q

Idiosyncratic

A

Genetic variations in genes coding for proteins which are not drug target or pharmacokinetic pathways - but could cause side effects

  • Ex: urticaria, anaphylaxis etc
  • Ex: In favism (G6PD): antimalarial drugs++=> hemolysis
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8
Q

Difficulties of pharmacogenomic researches

A

1) Phenocopy
2) Gene-gene interactions
3) Ethnic differences

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9
Q

Phenocopy in pharmacogenomics

A

Environmental factors can cause similar effects as the genetic variants
- Problem in pharmacogenomics

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10
Q

SNP map prediction of medicine response

A

1) Location of SNP on human DNA
2) Look at SNP genotype of patients with effective clinical trial vs those without - find diff. SNP
3) Isolate these SNP’s and perform clinical trial - predicting efficacy in one nucleotide variant, and no efficacy in the other
* Se bilde ipad

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11
Q

FDA

A

Food and Drug Administration

  • Agency in USA
  • Most connected to oncology, then psychiatry
  • Ca. 50 % of genes belong to CYP family
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12
Q

Suxamethonium chloride/suxamethonium/succinylcholine

A

Nicotinic acetylcholine receptor agonist (!)

  • Induce muscle relaxation - used in mild anesthesia
  • Ex: during intubation
  • Butyrylcholinesterase hydrolyses it
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13
Q

Mercaptopurine

A

Immunosuppressive drug

  • Used to treat e.g leukemia
  • TPMT: thiopurine methyltransferase metabolizes it
  • 3 known variants cause enzyme deficiency
  • Dangerous myelosuppression
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14
Q

CYP (cytochrome P-450) gene family

A
  • 57 members
  • In liver
  • Oxidize endogenous compounds and xenobiotics
  • Variants in this gene are responsible for 80 % (!) of all adverse drug responses
  • Most important: CYP2D6 & CYP2C19 (& CYP2C8/9)
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15
Q

CYP2D6 metabolism in the population

A
  • 35 %: carriers of non-functional 2D6 allele
  • 10 %: slow acting form
  • 7 %: super-fast acting form
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16
Q

CYP2C9 metabolism in population

A

Ca. 10 % are carriers of at least one allele of slow-metabolizing form
- May be treatable with only 50 % of normal dose

17
Q

Warfarin

A

Anticoagulant - vit. K antagonist

  • Oral: prevention of thrombosis and thromboembolism
  • Risk of severe bleeding: 1-3 %
  • CYP2C9 polymorphism explain 10% of dose variation
  • VKORC1 polymorphism explain 30% of dose var.
18
Q

Test for gene variations CYP450

A

AmpliChip CYP450 Test

19
Q

Statins

A

HMG-CoA reductase inhibitors

  • Lower cholesterol
  • Side effect: muscle damage (rare)
  • CYP enzymes important in metabolism
20
Q

Pharmakokinetics of statins

A

Metabolism: CYP3A5

  • Only 10 % of EU population show high CYP3A5 expression - in these: treatment less effective
  • 6986 G/A SNP in intron 3

Bile elimination: ABCB1

  • Multidrug resistance-1 (MDR-1)
  • C3435 SNP influenced the LDL-C level in atorvastatin therapy
21
Q

SEARCH

A

“Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine”

  • GWAS (genome wide association study)
  • A SNP in SLCO1B1 (SLCO1B1*5) - associated with statin-induced myopathy (SLCO genes play role in transport of statins)
22
Q

Pharmacodynamics of statins

A
  • Inhibits HMG-CoA
  • Lower cholesterol
  • Genes such as LDLR, SREBP, ApoE, CYP7A1 plays a role
23
Q

Pharmacogenomics in asthma

A

Salbutamol (INN) / Albuterol (USAN) is a short-acting
β2-adrenergic R agonist - bronchodilator
- Adverse effects in Arg/Arg patients rather than Gly/Gly at position 16

Other drugs:

  • Montelukast
  • Pranlukast
  • Zafirlukast
  • Block CysLT1
  • Zileuton
  • ABT-761
  • Inhibit 5-lipoxygenase
24
Q

ALOX5 gene

A

Promoter VNTR polymorphism

  • Wild: more VNTR, mutant: less
  • Substrate: arachidonic acid
  • Some asthma patients carry mutant type - can be a link
  • Mutant allele people have generally thicker carotid arteries (intima-media thickness) - effect decreased by Omega-3 FAs intake (in homozygous ALOX5VNTR)
25
Q

Nutrigenomics

A

How the nutrition influences the gene expression

26
Q

Nutrigenetics

A

How the genetic variations influence the effect of nutrition

27
Q

Advantages of nutrigenomics

A

1) Personalized nutrition
2) Better physical and mental health
3) Symptoms of several diseases can be attenuated or prevented
4) Lower health care costs

28
Q

Favism

A

G6PD deficiency: X linked

  • Protection against malaria
  • Hemolytic response to consumption of broad bean and certain medicines (antimalarial drugs f.ex)
29
Q

APOE

A

Apolipoprotein E gene

  • 3 main isoforms: E2 (Cys-Cys), E3 (Cys-Arg), E4 (Arg-Arg)
  • Cholesterol lowering diet has poor response in E2, but good response in E4
30
Q

APOA2 gene

A
  • 265 T/C

- The -265C allele is associated with higher intake and obesity

31
Q

CPT1A gene

A

Mutation associated with hypoketotic hypoglycemia

  • Carnitine palmitoyltransferase 1 - mitochondrial long chain FA oxidation
  • In many Siberians
32
Q

Folate important for…

A

1) DNA synthesis (thymine and purine bases)
2) DNA repair (via homocysteine)
3) DNA methylation (via homocysteine)

33
Q

Homocysteine

A

Associated with increased cardiovascular risk

  • Endothelial cell injury
  • SM proliferation
34
Q

Degradation of alcohol

A
  • ADH and ALDH
  • ADH 3:
    - Gamma1: fast metabolism
    - Gamma2: slow metabolism (reduced risk of MI)
35
Q

GWAIS coffee drinking and Parkinson’s disease

A

“Genome wide association and interaction study”

  • GRIN2A: encodes NMDA-glutamate R subunit - variation in this can influence the risk of Parkinson’s disease in heavy (!) coffee drinkers
36
Q

Epigenetics and food

A

Food can modify genes through epigenetic processes
1) Free FA exposure: M1 polarized macrophages (pro-inflammatory) - can block insulin action

2) In mice: high-fat diet can alter sperm tsRNAs* => metabolic disorders (glucose intolerance) in offpring
* tsRNAs are involved in control of small RNA silencing

3) In mice: Low-protein diet female mice gets small offspring due to methylated ribosomal DNA

37
Q

Virgin olive oil

A

Can repress in vivo expression of several pro-inflammatory genes

Genetics 2017 (19 decks)

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