Azathioprine: the drug where one gene test was never enough

For decades the safety question before starting azathioprine was answered with a TPMT test. That answer was right as far as it went and incomplete in a way that mattered, and the gene that completed it is the reason this page shows two tables instead of one.

Also sold as: Imuran, Azamun, Azasan.

What azathioprine is

Azathioprine is an immunosuppressant, taken daily and usually for years. It holds down inflammatory bowel disease, autoimmune hepatitis and several rheumatological conditions, and it is used after transplantation. It is a thiopurine, meaning the body converts it through a chain of steps into metabolites that suppress dividing cells.

Why your genes come into it

Bone marrow is full of dividing cells, so the same mechanism that calms an overactive immune system can also flatten a blood count. Two enzymes decide how much of each dose reaches that endpoint, and they act at different steps. TPMT diverts thiopurines down a harmless route before they can be activated. NUDT15 intercepts the active form later, just before it is built into DNA. Low activity in either one means more active drug from the same tablet, and the visible result looks identical whichever enzyme is the cause. That is why a clean TPMT result never meant a clean thiopurine result, and why CPIC grades both genes in a single guideline.

What published guidance says

Two tables follow, one per gene, and each is written by CPIC on the assumption that the other gene is typical. That assumption is stated in the guidance itself and it is the reason to read them together rather than separately: if both results are reduced, neither table on its own describes your situation. This is restatement of published guidance for education, not a dose. Azathioprine dosing and its blood-count monitoring belong to the prescriber who started it.

NUDT15

If your NUDT15 result is	What that means	Published CPIC guidance
Indeterminate	Normal risk of thiopurine-related leukopenia, neutropenia and myelosuppression. CPIC's combined NUDT15+TPMT guidance, shown assuming TPMT is typical.	Per CPIC (A): "Based on TPMT, initiate therapy with standard starting dose (e.g., 2 mg/kg/day for autoimmune diseases). During therapy, adjust doses of azathioprine based on disease-specific guidelines. It usually takes at least 2 weeks to reach steady state after each dose adjustment."
Intermediate Metabolizer	Increased risk of thiopurine-related leukopenia, neutropenia and myelosuppression. CPIC's combined NUDT15+TPMT guidance, shown assuming TPMT is typical.	Per CPIC (A): "Initiate therapy with reduced starting doses (30-80% of standard starting dose) if standard starting dose is ≥2 mg/kg/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of azathioprine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment."
Normal Metabolizer	Normal risk of thiopurine-related leukopenia, neutropenia and myelosuppression. CPIC's combined NUDT15+TPMT guidance, shown assuming TPMT is typical.	Per CPIC (A): "Initiate therapy with standard starting dose (e.g., 2 mg/kg/day for autoimmune diseases). During therapy, adjust doses of azathioprine based on disease-specific guidelines. It usually takes at least 2 weeks to reach steady state after each dose adjustment."
Poor Metabolizer	Greatly increased risk of thiopurine-related leukopenia, neutropenia and myelosuppression. Fatal toxicity possible without dose decrease. CPIC's combined NUDT15+TPMT guidance, shown assuming TPMT is typical.	Per CPIC (A): "Consider alternative nonthiopurine immunosuppressant therapy."
Possible Intermediate Metabolizer	Increased risk of thiopurine-related leukopenia, neutropenia and myelosuppression. CPIC's combined NUDT15+TPMT guidance, shown assuming TPMT is typical.	Per CPIC (A): "Initiate therapy with reduced starting doses (30-80% of standard starting dose) if standard starting dose is ≥2 mg/kg/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of azathioprine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment."

TPMT

If your TPMT result is	What that means	Published CPIC guidance
Indeterminate	CPIC's combined TPMT+NUDT15 guidance, shown assuming NUDT15 is typical.	Per CPIC (A): "Based on NUDT15, initiate therapy with standard starting dose (e.g., 2 mg/kg/day for autoimmune diseases). During therapy, adjust doses of azathioprine based on disease-specific guidelines. It usually takes at least 2 weeks to reach steady state after each dose adjustment."
Intermediate Metabolizer	TPMT IMs have moderate to high erythrocyte concentrations of TGN metabolites and low concentrations of MeMPNs compared to TPMT NMs. CPIC's combined TPMT+NUDT15 guidance, shown assuming NUDT15 is typical.	Per CPIC (A): "Initiate therapy with reduced starting doses (30-80% of standard starting dose) if standard starting dose is ≥2 mg/kg/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of azathioprine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment."
Normal Metabolizer	TPMT NMs have lower erythrocyte concentrations of TGN metabolites and higher concentrations of MeMPNs compared to TPMT IMs and TPMT PMs. This is the 'normal' pattern. CPIC's combined TPMT+NUDT15 guidance, shown assuming NUDT15 is typical.	Per CPIC (A): "Initiate therapy with standard starting dose (e.g., 2 mg/kg/day for autoimmune diseases). During therapy, adjust doses of azathioprine based on disease-specific guidelines. It usually takes at least 2 weeks to reach steady state after each dose adjustment."
Poor Metabolizer	TPMT PMs have extremely high erythrocyte concentrations of TGN metabolites and no MeMPN compared to TPMT NMs. CPIC's combined TPMT+NUDT15 guidance, shown assuming NUDT15 is typical.	Per CPIC (A): "Consider alternative nonthiopurine immunosuppressant therapy."
Possible Intermediate Metabolizer	TPMT IMs have moderate to high erythrocyte concentrations of TGN metabolites and low concentrations of MeMPNs compared to TPMT NMs. CPIC's combined TPMT+NUDT15 guidance, shown assuming NUDT15 is typical.	Per CPIC (A): "Initiate therapy with reduced starting doses (30-80% of standard starting dose) if standard starting dose is ≥2 mg/kg/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of azathioprine based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 2-4 weeks of stable dosing to reach steady state after each dose adjustment."

Can your DNA file answer this?

The two genes are not equally readable from consumer data, which is worth knowing before you go looking. NUDT15 is answerable from a plain 23andMe or AncestryDNA export, because its main no-function allele is tagged by a single position, rs116855232, that consumer arrays commonly carry. TPMT is not: it is graded on star-allele combinations built from several variants, so Aimosti reads it from aligned reads in a BAM or CRAM file as part of the Deep Read panel. A partial answer is still an answer, but half of this picture is the half that consumer chip data can give you. If a thiopurine is actually being started, the test to rely on is the clinical one the prescriber orders, often alongside a direct measurement of TPMT enzyme activity.

A genotyping chip reads only a few hundred thousand pre-selected positions, about 0.02% of your genome, chosen for common variation. It does not sequence the rest, so it cannot find the rare or novel pathogenic variants the clinical and carrier modules look for: a “no finding” from chip data means “this chip never looked”, far more so than with whole-genome sequencing. Chip data suits common-variant traits, pharmacogenomic tag SNPs, and haplogroup ancestry, not clinical or carrier screening.

See how Aimosti reports it

Common questions

My clinic tested TPMT and it was normal. Why does NUDT15 matter?

Because the two enzymes act at different steps, so a normal result for one carries no information about the other. NUDT15 was identified later, which is why plenty of people were tested for TPMT alone and told they were clear. Reduced-function NUDT15 alleles are considerably more common in East Asian and Hispanic populations, which is where a TPMT-only strategy left the biggest gap.

Does a normal result for both genes mean azathioprine is safe for me?

It means the two best-characterised genetic risk factors are absent. It does not remove the need for blood-count monitoring, because most of the reasons counts fall on a thiopurine have nothing to do with either gene. Anyone on azathioprine gets monitored regardless of genotype.

Why does the guidance mention mercaptopurine and thioguanine too?

They travel the same metabolic road and are graded in the same CPIC guideline, so a result that changes azathioprine changes them as well. The dose arithmetic differs between the three drugs, which is why CPIC writes a separate recommendation for each rather than one shared line.

Can I use my old DNA file instead of the clinical test?

Not as a substitute. If azathioprine is being started, the prescriber should order the clinical test, and an enzyme-activity measurement adds something no genotype can, because activity is affected by things other than the gene. A re-analysis of a file you already own is context and a reason to ask the question, not a clinical result.