Genetic Basis of Drug Response

Intro to Pharmacogenomics - Gene-Drug Dance

• Pharmacogenomics (PGx): How an individual's genetic makeup (genome) influences their drug response. The "Gene-Drug Dance."
• Core: Genetic variations (e.g., SNPs, CNVs) significantly alter:
  • Pharmacokinetics (PK): Affecting drug ADME, especially metabolism (e.g., CYP450 enzymes like CYP2D6, CYP2C19).
  • Pharmacodynamics (PD): Modifying drug targets (receptors, enzymes), changing drug sensitivity or effect.
• Goal: Personalized medicine-optimizing drug choice & dosage for maximal efficacy, minimal Adverse Drug Reactions (ADRs).

⭐ Variations in TPMT gene are critical for thiopurine drug (e.g., azathioprine) dosing, preventing severe myelosuppression.

Pharmacokinetic Variations - ADME Gene Twists

ADME gene variants alter drug PK, impacting efficacy & toxicity.

• Absorption (A):
  • SLCO1B1 (OATP1B1): Simvastatin uptake. *5 variant → ↑myopathy.
• Distribution (D):
  • ABCB1 (MDR1/P-gp): Efflux pump; affects digoxin, CNS drug levels.
• Metabolism (M) - Key Area:
  • Phase I (CYP450s):
    • CYP2D6: Codeine (PM→no effect; UM→toxicity), tamoxifen (activation).
    • CYP2C9: Warfarin (*2,*3→↓metab, ↑bleed, dose ↓), phenytoin.
    • CYP2C19: Clopidogrel (PM→↓active drug, ↑MACE), omeprazole.
    • CYP3A4/5: Metabolizes ~50% drugs (e.g., tacrolimus, statins).
  • Phase II (Conjugation):
    • UGT1A1: Irinotecan (*28 variant→↑toxicity), atazanavir.
    • TPMT: Thiopurines (azathioprine, 6-MP). Low activity→myelosuppression.
    • NAT2: Isoniazid (Slow acetylators→toxicity; Fast→↓efficacy).
• Excretion (E):
  • Renal transporters (OCT2, MATE1): Metformin clearance.

⭐ TPMT gene testing is vital pre-thiopurines (azathioprine, 6-MP). Deficient individuals (0.3%) are at high risk for severe myelosuppression; heterozygotes (10%) require dose ↓ reduction.

Pharmacodynamic & HLA - Target & Immune Gene Alerts

• Target Gene Variants: Alter drug efficacy/toxicity by modifying drug targets.
  • VKORC1: Affects warfarin dose (target: Vit K epoxide reductase).
  • HER2/neu (ERBB2): Predicts trastuzumab response (target: HER2 receptor).
  • ADRB2: Influences albuterol efficacy (target: β2-adrenergic receptor).
• HLA Alleles & Immune ADRs: Specific HLA types ↑ risk of severe drug hypersensitivity.
  • HLA-B*57:01: Abacavir hypersensitivity. Screen! (📌 ABC = Allele Before Commencing).
  • HLA-B*15:02: Carbamazepine-SJS/TEN in Asians. Screen!
  • HLA-A*31:01: Carbamazepine hypersensitivity (e.g., DRESS) in Europeans.
  • HLA-B*58:01: Allopurinol-SCARs (Severe Cutaneous Adverse Reactions). Screen!

⭐ HLA-B*15:02 screening is critical before carbamazepine in Asian patients to prevent SJS/TEN.

Clinical PGx Examples - Bedside Gene Guides

• Warfarin: CYP2C9, VKORC1 variants affect dose. ↑ Bleeding risk.
• Clopidogrel: CYP2C19 (poor metabolizers). ↓ Efficacy, ↑ CV events. Consider alternatives.
• Abacavir: HLA-B*57:01. Test before use. Positive? Contraindicated (↑ HSR risk).
• Azathioprine/6-MP: TPMT, NUDT15 deficiency. ↑ Myelosuppression. Dose reduction needed.
• Carbamazepine: HLA-B*15:02 (Asians). ↑ SJS/TEN risk. Screen prior to therapy.
• Codeine: CYP2D6 UMs (↑ morphine, toxicity), PMs (↓ analgesia).

⭐ HLA-B*57:01 testing is mandatory before initiating abacavir to prevent potentially fatal hypersensitivity reactions.

High‑Yield Points - ⚡ Biggest Takeaways

• Genetic variations critically impact drug efficacy and adverse reactions.
• CYP2D6 polymorphisms alter metabolism of codeine, tamoxifen, and many psychotropics.
• CYP2C19 variants affect clopidogrel activation and PPI metabolism.
• TPMT/NUDT15 variants ↑ risk of thiopurine (azathioprine, 6-MP) toxicity.
• HLA-B*5701 screening is crucial before abacavir to prevent hypersensitivity.
• SLCO1B1 (OATP1B1) variants ↑ risk of statin-induced myopathy.
• VKORC1 and CYP2C9 genotypes guide warfarin dosing.