Pharmacogenomic Testing

Pharmacogenomic Testing - Genes Guiding Drugs

• Pharmacogenomics (PGx): The study of how an individual's genetic makeup influences their response to drugs.
• PGx Testing: Genotyping specific genes to guide drug selection and dosing, aiming to predict efficacy and ADR risk.
• Primary Goals:
  • Maximize therapeutic efficacy.
  • Minimize/prevent Adverse Drug Reactions (ADRs).
• Core Concepts:
  • Genetic Polymorphism: Common DNA variations (e.g., Single Nucleotide Polymorphism (SNP), Variable Number Tandem Repeats (VNTR), Copy Number Variations (CNV)).
  • Allele: A specific version of a gene.
  • Genotype: An individual's pair of alleles for a particular gene.
  • Phenotype: Observable characteristic resulting from genotype (e.g., drug metabolizer status: Poor (PM), Intermediate (IM), Extensive (EM), Ultra-rapid (UM)).

⭐ Pharmacogenomics aims to tailor drug therapy at the individual level based on genetic makeup.

Key Gene Players - Enzyme & Allele Action

Lab Test Lineup - Spotting Gene Variants

• Samples: Blood, saliva/buccal swab.
• Approaches:
  • Pre-emptive: Test before drug Rx.
  • Reactive: Test after ADR/failure.
• Methods:
  • PCR-RFLP: Detects known SNPs via enzyme digestion.
  • Real-time PCR (TaqMan): Rapid genotyping of known variants.
  • DNA Microarrays: Screens many known pharmacogenes/SNPs.
  • NGS: Comprehensive; finds known & novel variants.

⭐ Genotyping for specific Single Nucleotide Polymorphisms (SNPs) is the most common approach in current clinical pharmacogenomic testing due to its cost-effectiveness for known variants.

Bedside Gene Clues - Real-World Impact

Pharmacogenomic tests guide drug selection & dosing, minimizing adverse drug reactions (ADRs) & maximizing efficacy.

• Warfarin: CYP2C9 (metabolism) & VKORC1 (target) variants necessitate dose adjustments. 📌 Warfarin needs Careful Versioning.
• Clopidogrel: CYP2C19 loss-of-function alleles (e.g., *2, *3) → reduced antiplatelet effect, ↑ risk of stent thrombosis.
• Abacavir: HLA-B*57:01 positive mandates avoidance. Screening prevents severe hypersensitivity syndrome (HSR).

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

• Irinotecan: UGT1A1*28 variant (Gilbert's syndrome link) → ↑ risk of severe neutropenia/diarrhea.
• Statins (e.g., Simvastatin): SLCO1B1 (OATP1B1 transporter) variants → ↑ risk of myopathy.
• Azathioprine/6-Mercaptopurine: TPMT or NUDT15 deficiency → ↑ risk of severe myelosuppression. Dose reduction ~90% for homozygous deficient.

High‑Yield Points - ⚡ Biggest Takeaways

• CYP2D6 variants impact codeine efficacy and toxicity; ultra-rapid metabolizers risk opioid toxicity.
• CYP2C19 loss-of-function alleles reduce clopidogrel activation, increasing thrombotic risk.
• TPMT/NUDT15 testing is crucial before thiopurine therapy to prevent severe myelosuppression.
• HLA-B*5701 screening is mandatory before abacavir to avoid hypersensitivity reactions.
• HLA-B*1502 is associated with carbamazepine-induced SJS/TEN in specific populations.
• VKORC1 and CYP2C9 genotypes guide initial warfarin dosing.
• SLCO1B1 variants increase risk of statin-induced myopathy.