14. Pharmacogenomics and nutrigenomics (wk11) Flashcards
2 main goals of pharmacogenomics
1) Search for new drugs and drug targets
2) Influence of genetic variations on drug response in patients
Protein coding genes vs drug targets
400 drug targets
20 000 protein coding genes (and RNA etc)
At least 10x more drug targets than today
Drug response pharmacogenomics
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
Pharmacodynamics
What the drug does to the body
Pharmacokinetics
What the body does to the drug ADME: - A: absorption - D: distribution - M: metabolism - E: elimination
Pharmacogenomics
How genetic variations in the pharmacokinetic and pharmacodynamic processes influence the effect and side effect of the drugs
Idiosyncratic
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
Difficulties of pharmacogenomic researches
1) Phenocopy
2) Gene-gene interactions
3) Ethnic differences
Phenocopy in pharmacogenomics
Environmental factors can cause similar effects as the genetic variants
- Problem in pharmacogenomics
SNP map prediction of medicine response
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
FDA
Food and Drug Administration
- Agency in USA
- Most connected to oncology, then psychiatry
- Ca. 50 % of genes belong to CYP family
Suxamethonium chloride/suxamethonium/succinylcholine
Nicotinic acetylcholine receptor agonist (!)
- Induce muscle relaxation - used in mild anesthesia
- Ex: during intubation
- Butyrylcholinesterase hydrolyses it
Mercaptopurine
Immunosuppressive drug
- Used to treat e.g leukemia
- TPMT: thiopurine methyltransferase metabolizes it
- 3 known variants cause enzyme deficiency
- Dangerous myelosuppression
CYP (cytochrome P-450) gene family
- 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)
CYP2D6 metabolism in the population
- 35 %: carriers of non-functional 2D6 allele
- 10 %: slow acting form
- 7 %: super-fast acting form
CYP2C9 metabolism in population
Ca. 10 % are carriers of at least one allele of slow-metabolizing form
- May be treatable with only 50 % of normal dose
Warfarin
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.
Test for gene variations CYP450
AmpliChip CYP450 Test
Statins
HMG-CoA reductase inhibitors
- Lower cholesterol
- Side effect: muscle damage (rare)
- CYP enzymes important in metabolism
Pharmakokinetics of statins
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
SEARCH
“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)
Pharmacodynamics of statins
- Inhibits HMG-CoA
- Lower cholesterol
- Genes such as LDLR, SREBP, ApoE, CYP7A1 plays a role
Pharmacogenomics in asthma
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
ALOX5 gene
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)
Nutrigenomics
How the nutrition influences the gene expression
Nutrigenetics
How the genetic variations influence the effect of nutrition
Advantages of nutrigenomics
1) Personalized nutrition
2) Better physical and mental health
3) Symptoms of several diseases can be attenuated or prevented
4) Lower health care costs
Favism
G6PD deficiency: X linked
- Protection against malaria
- Hemolytic response to consumption of broad bean and certain medicines (antimalarial drugs f.ex)
APOE
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
APOA2 gene
- 265 T/C
- The -265C allele is associated with higher intake and obesity
CPT1A gene
Mutation associated with hypoketotic hypoglycemia
- Carnitine palmitoyltransferase 1 - mitochondrial long chain FA oxidation
- In many Siberians
Folate important for…
1) DNA synthesis (thymine and purine bases)
2) DNA repair (via homocysteine)
3) DNA methylation (via homocysteine)
Homocysteine
Associated with increased cardiovascular risk
- Endothelial cell injury
- SM proliferation
Degradation of alcohol
- ADH and ALDH
- ADH 3:
- Gamma1: fast metabolism
- Gamma2: slow metabolism (reduced risk of MI)
GWAIS coffee drinking and Parkinson’s disease
“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
Epigenetics and food
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
Virgin olive oil
Can repress in vivo expression of several pro-inflammatory genes
