Biochemistry of Pharmacogenomics (finished)

• Sickle Cell Disease (SCD) is an autosomal recessive trait where the person has a single nucleotide polymorphism (SNP) in hemoglobin beta genes (c.20A>T)
• A to T substitution in sickle cell disease will produce a single amino acid change of glutamic acid to valine

  • Changes protein folding to where hemoglobin has a lower affinity to oxygen called anemia
• Hbs is the nomenclature for mutated hemoglobin
• Sickle-shaped RBCs can distrub or obstruct the capillaries by restricting blood flow to organs
• Sickle cell disease is an example of a point mutation
• Symptoms of SCD:

  • hypoxia
  • fatigue
  • pain from obstruction of small vessels
  • recurrent infections
  • enlarged spleen
  • stroke
• Treatment of SCD:

  • no curative treatment
  • symptomtic pain relief
  • stroke prevention
  • infection prevention
  • chronic transfusion
• Down syndrome is an example of chromosomal aneuploidy with an extra chromosome 21 (trisomy)
• CYP2C19 c.636G>A (p.Trp212Ter) means:

  • G to A substitution at the coding DNA position 636 in the CYP2C19 gene
  • p.Trp212Ter means the amino acid Trp at position 212 is changed to a stop codon (nonsense variant)
• Pharmacogenomics is the study of how genetic variation changes a person's response to medicine

  • This includes how well it works and whether it is harmful to the person
• Pharmacogenomics is annotated as PGx
• Identifying genetic variants in patients in advance can help us subdivide patients with the same diagnosis into subgroups based on what treatment would work best for them
• Pharmacokinetics: the course of the medication and their metabolite levels in the body with drug absorption, distribution, metabolism, and elimination (ADME)
• Pharmacodynamics: pharmacological effect of a drug on the body which can be either desire or undesired - related to interactions between drugs and drug target or how drugs can affect the body
• Pharmacogenetics has two categories:

  • Pharmacodynamics
  • Pharmacokinetics
• Variability in drug matbolizing enzymes and drug transporters often contributes to variability in pharmacokinetics due to affects on metabolism, activity of medications, or distributions of medication by affecting transportersor metabolizing enzymes
• Drug targets can contribute to inter-individual variability in pharmacodynamics and genetic variants in drug target genes - this may affect drug efficacy and/or toxicity
• Drug transporters can affect the distribution or the pharmodynamics of the drug
• Variants in drug metabolizing enzymes are the major genetic variants that can affect pharmacokinetics of drugs

  • Ex.: genetic variants in CYP enzyme genes
• Genetic variants may influence drug pharmokinetics or pharmacodynamics

  • Ex.: genetic variants in SLCO1B1 (take up of statins) or SLC6A4 (anti-depressant that interacts with serotonin) genes
• Drugs targets include:

  • Receptors (i.e. beta-1-adrenergic receptor gene)
  • Proteins in signaling pathway (i.e. BRAF gene)
  • Enzymes (i.e. VKORC1 gene)
  • Transporters
• Pharmacogenomics of proteins in signaling pathways are extensively studied in oncology
• Cell signaling is used for monitoring and responding to their environment

  • Important for regulation of cell growth, division, differentiation, and behavior
• Cell Signaling Steps:

  1. Extracellular ligand binds to receptor protein
  2. Receptor activates one or more intracellular signaling proteins (i.e. kinase proteins)
  3. Activation of effector proteins
  4. Activation of physiological functions
• When there's a change in structure for a receptor/protein, there is likely a change in function as well
• G protein coupled receptors are the largest receptors in the human body
• G proteins are made up of alpha, beta, gamma subunits
• G protein types:

  • Gs: G stimulating protein (activates adenyl cyclase and increases cAMP to activate a downstream signaling pathway)
  • Gi: G inhibitory protein (inhibits adenyl cyclase and decreases the activation of downstream signaling pathways)
• Beta1-Adrenergic Receptor (ADRB1):

  • Gs protein receptor
  • Endogenous ligands: epinephrine, norepinephrine
  • Expressed in cardiac and renal tissues
• ADRB1 in cardiac tissues:

  • Increases heart rate
  • Increases contractility
  • Increases blood pressure
• ADRB1 in renal tissue: increase renin-angiotensin-aldosterone system (RAAS)
• ADRB1 common variants:

  • p.Ser49Gly (c.145 A>G, rs1801252)
  • p.Arg389Gly (c.1165 C>G, rs1801253)
• Beta-blockers are antagonists of beta-adrenergic receptors
• Beta-blocker effects:

  • Decrease heart rate (decrease chronotropic)
  • Decrease contractility (decrease iontropic)
  • Decrease blood pressure
• Common indications of beta-blockers: heart failure, ischemic heart disease, hypertension
• Arg389Gly polymorphism in ADRB1: located in intracellular are at G-protein domain

  • Impact: decreased coupling to Gs, lower blood pressure, heart rates, lower cAMP
• Gly389 allele has a poor response to beta-blockers compared to Arg389 allele
• Blood pressure response to a beta-blocker is significantly decreases in patients with a Gly389Gly than a Gly389Arg or a Arg389Arg
• Epidermal growth factor receptor (EGFR) are receptor tyrosine kinases (RTKs)
• Receptor tyrosine kinases (RTKs) activate downstream signaling pathways to lead towards cell survival, proliferation, growth, or differentiation