Pharmacogenetics and Personalized Medicine

Pharmacogenetics Basics - Gene-Drug Dance Intro

• Pharmacogenetics (PGt): How single genes affect drug response; specific gene-drug interactions.
• Pharmacogenomics (PGx): Broader; how genome (all genes) affects drug response.
• Goal: Tailor drug choice & dose to individual genetic makeup.
  • Maximise efficacy.
  • Minimise adverse drug reactions (ADRs).
• Foundation of Personalized Medicine: Right drug, right dose, right patient.
• Genetic variations (e.g., SNPs) alter drug ADME & drug targets.

⭐ PGt/PGx aims to predict if a drug will be effective or cause side effects before it's prescribed.

Genetic Variations - DNA's Drug Twists

• Principle: Inherited DNA sequence changes cause inter-individual differences in drug response.
• Major Types of Variations:
  • SNPs (Single Nucleotide Polymorphisms): Most frequent; single base-pair substitutions (e.g., C→T).
  • Indels: Small insertions or deletions of DNA bases.
  • CNVs (Copy Number Variations): Duplication or deletion of larger DNA segments, affecting gene dosage.
• Consequences:
  • Altered drug metabolism (e.g., CYP enzymes).
  • Modified drug transporter function.
  • Changes in drug target sensitivity.

⭐ TPMT gene variations: Predict thiopurine (e.g., azathioprine, 6-mercaptopurine) toxicity. Low TPMT activity leads to ↑ risk of myelosuppression.

Key Pathways & Players - Metabolism's Genetic Code

• Cytochrome P450 (CYPs): Key drug metabolizers.
  • CYP2D6: Codeine (↓ analgesia), tamoxifen (↓ efficacy).
  • CYP2C9: Warfarin (↑ bleeding risk with *2, *3 variants).
  • CYP2C19: Clopidogrel (↓ effect with *2, *3; "resistance").
• Other Enzymes:
  • TPMT (Thiopurine S-Methyltransferase): Azathioprine, 6-MP (↑ myelosuppression with low activity).
  • UGT1A1: Irinotecan (↑ toxicity with *28 allele), bilirubin.
• Transporters:
  • SLCO1B1 (OATP1B1): Statins (simvastatin, ↑ myopathy with 521T>C).
  • ABCB1 (MDR1/P-glycoprotein): Digoxin (altered levels).

⭐ TPMT testing is crucial before initiating thiopurines (azathioprine, 6-MP) to prevent severe myelosuppression in deficient individuals.

Clinical Applications - Genes Guiding Doses

• Warfarin: CYP2C9 (metabolism) & VKORC1 (sensitivity) variants guide dose.
  • ↓ function alleles require ↓ dose to reduce bleeding risk.
• Clopidogrel: CYP2C19 activates prodrug.
  • Poor metabolizers (PMs): ↓ efficacy, ↑ MACE. Alt: prasugrel, ticagrelor.
• Abacavir: HLA-B*5701 testing mandatory.
  • Positive: high HSR risk; contraindicated.

⭐ HLA-B*1502 screening in Asians for Carbamazepine is crucial to prevent SJS/TEN.

• Azathioprine/6-MP: TPMT/NUDT15 variants affect metabolism.
  • ↓ enzyme activity: ↑ myelosuppression risk. Dose reduction vital.
• Codeine: CYP2D6 metabolizes to morphine.
  • Ultra-rapid metabolizers (UMs): ↑ toxicity risk. Poor metabolizers (PMs): ↓ analgesia.

Future & Hurdles - Tailored Meds Ahead

• Future Scope:
  • AI/ML for drug development & patient selection
  • Polygenic Risk Scores (PRS) for disease prediction
  • Advanced gene editing (e.g., CRISPR)
  • Seamless PGx data integration in EHRs
• Key Hurdles:
  • Ethical, Legal, Social Implications (ELSI)
  • High costs & reimbursement issues
  • Clinical implementation & workforce training
  • Data security & privacy concerns
  • Managing complex gene-environment interactions

⭐ Pre-treatment screening for HLA-B*5701 is crucial to prevent abacavir hypersensitivity.

High‑Yield Points - ⚡ Biggest Takeaways

• Genetic variations (e.g., SNPs, CYP2D6, TPMT) significantly alter drug efficacy and toxicity.
• CYP2D6 polymorphisms impact metabolism of codeine, tamoxifen, and many beta-blockers.
• TPMT deficiency ↑ mercaptopurine toxicity (e.g., myelosuppression); genotyping crucial.
• Warfarin dosing is guided by CYP2C9 & VKORC1 variants for optimal anticoagulation.
• HLA-B*5701 screening is vital before abacavir to prevent severe hypersensitivity.
• Clopidogrel efficacy ↓ in CYP2C19 poor metabolizers.
• Personalized medicine optimizes drug therapy using an individual's genetic profile.