Non-CYP450 Pharmacogenomic Associations for the USMLE
Beyond the CYP450 enzymes, several genes strongly predict adverse drug reactions and toxicity. The unifying framework is simple: a specific gene variant alters how a patient handles a specific drug, producing a characteristic, often severe, adverse effect. On the exam, recognize the gene–drug–toxicity triad and, when relevant, the population at risk or the need for mandatory pre-treatment screening.
TPMT — Thiopurine Toxicity
TPMT metabolizes the thiopurine drugs 6-mercaptopurine and azathioprine. Patients with low TPMT activity cannot adequately clear these agents, leading to drug accumulation and severe myelosuppression. Suspect a TPMT-related problem when a patient on a thiopurine develops profound bone marrow suppression.
UGT1A1 — Irinotecan and Gilbert Syndrome
UGT1A1 is the glucuronidation enzyme that is also deficient in Gilbert syndrome. Patients with reduced UGT1A1 activity (Gilbert syndrome) who receive irinotecan experience increased toxicity because the drug and its active metabolite are cleared less efficiently. Link the classic unconjugated hyperbilirubinemia patient to heightened irinotecan risk.
HLA-B*5701 — Abacavir Hypersensitivity
HLA-B*5701 is associated with abacavir hypersensitivity reaction. This is a rare but exam-favorite instance of mandatory pharmacogenomic screening: patients must be tested for HLA-B*5701 before starting abacavir, and carriers should not receive the drug.
HLA-B*1502 — Carbamazepine and Stevens-Johnson Syndrome
HLA-B*1502 predisposes to Stevens-Johnson syndrome (and severe cutaneous reactions) with carbamazepine. This association is particularly relevant in Asian populations, where screening is emphasized before initiating carbamazepine. Distinguish this from the HLA-B*5701/abacavir pairing — both are HLA-linked, but the drug and reaction differ.
G6PD — Oxidative Hemolysis
G6PD-deficient patients develop hemolytic anemia when exposed to oxidative stressors, including primaquine, sulfonamides, and dapsone. G6PD deficiency is X-linked recessive, so affected patients are predominantly male. Recognize the drug-induced hemolysis vignette in a patient given an antimalarial or a sulfa drug.
NAT2 — Isoniazid Acetylation
NAT2 acetylates isoniazid. Slow acetylators clear isoniazid less efficiently, increasing the risk of peripheral neuropathy. This is why the neuropathy classically associated with isoniazid disproportionately affects slow acetylators.
High-yield
- Gene–drug–toxicity triad is the tested unit: match each gene to its drug and its characteristic adverse effect.
- TPMT low activity → severe myelosuppression with 6-mercaptopurine/azathioprine.
- UGT1A1 deficiency (Gilbert syndrome) → increased irinotecan toxicity.
- HLA-B*5701 → abacavir hypersensitivity; screening is mandatory before use.
- HLA-B*1502 → carbamazepine-induced Stevens-Johnson syndrome, especially in Asian populations.
- G6PD deficiency → hemolytic anemia with primaquine, sulfonamides, and dapsone; X-linked recessive.
- NAT2 slow acetylators → increased isoniazid-induced peripheral neuropathy.
Pitfalls
- Confusing the two HLA associations — HLA-B*5701 is abacavir hypersensitivity, HLA-B*1502 is carbamazepine/Stevens-Johnson syndrome.
- Forgetting that these are non-CYP450 associations and reaching for CYP-based explanations (e.g., codeine, clopidogrel, warfarin) when the stem points to TPMT, UGT1A1, HLA, G6PD, or NAT2.
- Overlooking the Gilbert syndrome link when assessing irinotecan toxicity risk.
- Assuming G6PD deficiency affects both sexes equally — it is X-linked recessive and predominantly affects males.
- Missing that HLA-B*1502 carbamazepine risk is emphasized in Asian populations.
Clinical pearls
- Profound cytopenias in a patient started on azathioprine or 6-MP should trigger thought of low TPMT activity.
- Test for HLA-B*5701 before ever prescribing abacavir — a rare example of required pre-treatment genetic screening.
- Hemolysis after an antimalarial or sulfa drug in a young man = G6PD deficiency.
- Isoniazid peripheral neuropathy is worse in NAT2 slow acetylators.
Frequently asked
Which gene must be screened before starting abacavir, and why?
HLA-B*5701. Carriers are at risk for a hypersensitivity reaction, so screening is mandatory and positive patients should not receive abacavir.
Why do Gilbert syndrome patients tolerate irinotecan poorly?
Gilbert syndrome reflects reduced UGT1A1 activity, the same enzyme needed to clear irinotecan and its active metabolite, resulting in increased toxicity.
A patient on azathioprine develops severe bone marrow suppression — which enzyme deficiency is responsible?
Low TPMT activity. TPMT metabolizes thiopurines (6-mercaptopurine, azathioprine); deficiency causes drug accumulation and severe myelosuppression.
How do the two HLA pharmacogenomic associations differ?
HLA-B*5701 is linked to abacavir hypersensitivity, whereas HLA-B*1502 is linked to carbamazepine-induced Stevens-Johnson syndrome, particularly in Asian populations.
Which drugs cause hemolytic anemia in G6PD-deficient patients?
Primaquine, sulfonamides, and dapsone. These oxidative stressors precipitate hemolysis in deficient patients, who are predominantly male because G6PD deficiency is X-linked recessive.
Why are NAT2 slow acetylators at higher risk on isoniazid?
NAT2 acetylates isoniazid; slow acetylators clear the drug less efficiently, increasing the risk of peripheral neuropathy.
What is the shared framework across all these associations?
Each pairs a specific gene variant with a specific drug and a predictable adverse effect. Identifying the gene–drug–toxicity triad, and any at-risk population or screening requirement, is the key exam skill.
Turn this into reasoning you can use on exam day — practice Non-CYP450 Pharmacogenomic Associations on branching cases where your decisions shape the patient.