Pharmacogenomics
Also known as: PGx, pharmacogenetics
The study of how genetic variants affect drug response — which patients metabolize drugs faster, slower, or differently due to inherited differences in drug-metabolizing enzymes.
Source: Relling MV & Klein TE. 'CPIC: Clinical Pharmacogenetics Implementation Consortium.' Clin Pharmacol Ther 2011;89(3):464-467. https://doi.org/10.1038/clpt.2010.279
Primary reference ↗Pharmacogenomics (PGx) studies how a person’s genetic makeup affects their response to drugs. The core insight: drug-metabolizing enzymes vary across individuals due to inherited genetic variants, causing the same dose to produce very different drug levels in different patients.
Key Enzyme Families
- CYP450s (cytochrome P450): CYP2C9, CYP2C19, CYP2D6, CYP3A4/5 — metabolize ~70% of clinically used drugs
- TPMT / NUDT15 — metabolize thiopurine drugs (6-mercaptopurine, azathioprine) used in cancer and autoimmune disease
- UGT1A1 — metabolizes irinotecan (colorectal cancer)
Clinical Metabolizer Categories
| Category | Phenotype | Drug effect |
|---|---|---|
| Poor metabolizer | Reduced/absent enzyme | Drug accumulates → toxicity risk |
| Intermediate metabolizer | Reduced enzyme | Partial accumulation |
| Normal metabolizer | Standard enzyme | Standard dosing |
| Rapid/ultrarapid metabolizer | Increased enzyme | Drug cleared quickly → underdosing risk |
CPIC Guidelines
The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes evidence-based prescribing guidelines based on genotype. CPIC guidelines mandate CYP2C9 genotyping for warfarin dosing — a carrier of CYP2C9*3 may need 80-90% dose reduction compared to a normal metabolizer.
VUS in Pharmacogenomics
Standard pharmacogenomic testing covers known alleles. Novel rare variants (VUS) that fall outside the tested panel require functional classification. This is where computational tools like ESM-2 provide provisional evidence while formal functional data is generated.