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Pharmacogenetics & Pharmacogenomics: Genes & Drug Response

14 Jun 2026 2 min read By admin

Why does one standard dose help one patient, do nothing for a second, and poison a third? Often the answer is in their genes. Pharmacogenetics studies how inherited variation shapes drug response — and the metaboliser spectrum below is where it starts.

Drug-metaboliser phenotypes (a standard active drug) ↑ drug level → toxicity ↓ drug level → failure Poor (PM) Intermediate Extensive(normal) Ultrarapid (UM) Metaboliser activity increases → Prodrugs (codeine → morphine) reverse this: PM → no analgesia; UM → morphine toxicity.
For an active drug, poor metabolisers accumulate it (toxicity) and ultrarapid metabolisers clear it (failure). Prodrugs flip the rule.

Definitions

  • Pharmacogenetics — the study of variation in a single gene (or a few) influencing drug response.
  • Pharmacogenomics — the broader, genome-wide study of how genes affect drug response (also used in drug discovery).
  • The shared goal is personalised / precision medicine — the right drug, at the right dose, for the right patient.

Types of genetic variation

  • Pharmacokinetic (metabolism): polymorphisms in metabolising enzymes (CYP450, NAT2, TPMT) alter drug levels.
  • Pharmacodynamic (target): variation in receptors/targets alters the drug effect.
  • Immunological (HLA): HLA alleles predict severe hypersensitivity reactions.

High-yield examples

Gene / enzymeDrugClinical effect
NAT2 (acetylation)IsoniazidSlow acetylators → neuropathy; fast → lower levels.
TPMTAzathioprine / 6-MPDeficiency → severe myelosuppression.
CYP2C9 + VKORC1WarfarinDetermines the dose requirement.
CYP2C19ClopidogrelPoor metabolisers → reduced efficacy.
CYP2D6CodeineUltrarapid → morphine toxicity; poor → no analgesia.
HLA-B*1502CarbamazepineStevens–Johnson syndrome (esp. Asians).
HLA-B*5701AbacavirHypersensitivity reaction.
G6PD deficiencyPrimaquine / dapsoneHaemolysis.
PseudocholinesteraseSuccinylcholineProlonged apnoea.

Applications

  • Dose individualisation — warfarin (CYP2C9/VKORC1), thiopurines (TPMT).
  • Avoiding ADRs — HLA testing before abacavir and carbamazepine.
  • Predicting efficacy — clopidogrel (CYP2C19), trastuzumab (HER2 status) and other companion diagnostics.
  • Drug development — target identification and stratified (“enriched”) trials.
Exam tip: pharmacogenetics = single gene, pharmacogenomics = genome-wide. Bank the pairings — NAT2→isoniazid, TPMT→azathioprine, CYP2C9/VKORC1→warfarin, CYP2C19→clopidogrel, CYP2D6→codeine, and the HLA links HLA-B*1502→carbamazepine (SJS) and HLA-B*5701→abacavir.

Pharmacogenetics is the engine of precision medicine — it explains unpredictable responses and turns a few genotype tests into safer, more effective prescribing.

Test yourself

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  1. Q1. HLA-B*1502 testing before which drug reduces the risk of Stevens–Johnson syndrome?

  2. Q2. A CYP2D6 ultra-rapid metaboliser given codeine is at risk of:

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