NUDT15: the thiopurine gene a TPMT test does not cover
For decades the thiopurine safety question was answered with a TPMT test alone. NUDT15 is the reason that answer was incomplete, and it is the more important of the two genes in much of the world.
Also known as: nudix hydrolase 15, MTH2.
What NUDT15 does
Thiopurine drugs are eventually converted into a form that gets built into DNA, which is how they suppress dividing cells. NUDT15 makes an enzyme that intercepts that active form before it can be incorporated. Less NUDT15 activity means more of the drug reaches DNA from the same dose, and the visible result is the same as a low TPMT result even though the mechanism sits at a different point in the chain. This is why a clean TPMT result never meant a clean thiopurine result.
The metabolizer groups
NUDT15 is graded by diplotype into normal, intermediate and poor metabolizer, with possible intermediate metabolizer for combinations whose function is not settled and Indeterminate where the pair cannot be graded. Most of the clinical signal comes from one no-function allele, *3. The frequency picture is what makes this gene matter: reduced-function NUDT15 alleles are much more common in East Asian and Hispanic populations than in European ones, which is precisely why a TPMT-only strategy left a gap.
Medications where it matters
azathioprine (Imuran)
Azathioprine is taken for years in inflammatory bowel disease, autoimmune conditions and transplant care. A reduced-function NUDT15 result raises the risk of the blood counts falling on a dose that most people tolerate, and it does so whether or not TPMT is normal.
| If your result is | Published CPIC guidance |
|---|---|
| Indeterminate | 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 | 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 | 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 | Per CPIC (A): "Consider alternative nonthiopurine immunosuppressant therapy." |
| Possible Intermediate Metabolizer | 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." |
mercaptopurine (6-MP)
In childhood leukaemia maintenance, where mercaptopurine is given for years, NUDT15 poor metabolizers were the patients who kept needing dose interruptions before anyone knew why. The guidance below reflects how large those reductions turned out to need to be.
| If your result is | Published CPIC guidance |
|---|---|
| Indeterminate | Per CPIC (A): "Based on TPMT, initiate therapy with standard starting dose of mecaptopurine (e.g., 75 mg/m2/day for malignancy or 1.5 mg/kg/day for nonmalignancy). During therapy, adjust the doses of myelosuppressive agents, as per standard clinical practice. It usually takes at least 2 weeks of stable dosing to reach steady state after each dose adjustment." |
| Intermediate Metabolizer | Per CPIC (A): "Initiate therapy with decreased starting doses (30-80% of standard starting dose) if starting dose is ≥75 mg/m2/day (for malignancy) or ≥1.5 mg/kg/day (for nonmalignancy). If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust mercaptopurine doses 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. If myelosuppression occurs, and the patient is on combination therapy, emphasis should be on reducing mercaptopurine over other agents." |
| Normal Metabolizer | Per CPIC (A): "Initiate therapy with standard starting dose of mecaptopurine (e.g., 75 mg/m2/day for malignancy or 1.5 mg/kg/day for nonmalignancy). During therapy, adjust the doses of myelosuppressive agents, as per standard clinical practice. It usually takes at least 2 weeks of stable dosing to reach steady state after each dose adjustment." |
| Poor Metabolizer | Per CPIC (A): "For malignancy: initiate therapy with drastically reduced starting doses. Reduce starting dose by 10-fold and reduce frequency to thrice weekly instead of daily (e.g. 10 mg/m2/day given 3 days/week). During therapy, adjust mercaptopurine doses based on the degree of myelosuppression and disease-specific guidelines. It usually takes at least 4-6 weeks of stable dosing to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignancy: consider alternative nonthiopurine immunosuppressant therapy." |
| Possible Intermediate Metabolizer | Per CPIC (A): "Initiate therapy with decreased starting doses (30-80% of standard starting dose) if starting dose is ≥75 mg/m2/day (for malignancy) or ≥1.5 mg/kg/day (for nonmalignancy). If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust mercaptopurine doses 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. If myelosuppression occurs, and the patient is on combination therapy, emphasis should be on reducing mercaptopurine over other agents." |
thioguanine (6-TG)
Thioguanine reaches the same active endpoint by a shorter route, so the same enzyme sets the same ceiling. It is here because a NUDT15 result that changes one thiopurine changes all three.
| If your result is | Published CPIC guidance |
|---|---|
| Indeterminate | Per CPIC (A): "Based on TPMT, initiate therapy with standard starting dose of thioguanine (e.g., 40 mg/m2/day for malignancy). During therapy, adjust the doses of myelosuppressive agents, as per standard clinical practice. It usually takes at least 2 weeks of stable dosing to reach steady state after each dose adjustment." |
| Intermediate Metabolizer | Per CPIC (A): "Initiate therapy with decreased starting doses (30-80% of standard starting dose) if standard starting dose is ≥40 mg/m2/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of thioguanine 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. If myelosuppression occurs, and the patient is on combination therapy, emphasis should be on reducing thioguanine over other agents." |
| Normal Metabolizer | Per CPIC (A): "Initiate therapy with standard starting dose of thioguanine (e.g., 40 mg/m2/day for malignancy). During therapy, adjust the doses of myelosuppressive agents, as per standard clinical practice. It usually takes at least 2 weeks of stable dosing to reach steady state after each dose adjustment." |
| Poor Metabolizer | Per CPIC (A): "Initiate therapy with drastically reduced starting doses. Reduce starting dose by 10-fold and reduce frequency to thrice weekly instead of daily. During therapy, adjust thioguanine doses based on degree of myelosuppression and disease-specific guidelines. It usually takes at least 4-6 weeks of stable dosing to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing thioguanine over other agents." |
| Possible Intermediate Metabolizer | Per CPIC (A): "Initiate therapy with decreased starting doses (30-80% of standard starting dose) if standard starting dose is ≥40 mg/m2/day. If starting dose is already below standard starting dose, dose reduction might not be necessary. During therapy, adjust the doses of thioguanine 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. If myelosuppression occurs, and the patient is on combination therapy, emphasis should be on reducing thioguanine over other agents." |
Is this in your raw DNA file?
NUDT15 is one of the pharmacogenes Aimosti can read from a plain consumer file. The *3 allele is tagged by a single position, rs116855232, which consumer genotyping arrays commonly carry, so this gene is part of the standard report rather than Deep Read only. Two limits are worth stating: the rarer NUDT15 alleles are not on the chip, and if the tagging position is absent from your export, the file cannot distinguish the reference allele from a position that was never read. The report says which of those it is rather than calling an unread position normal.
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.
Common questions
Is NUDT15 in my 23andMe or AncestryDNA raw data?
Usually. The main variant, rs116855232, is a common consumer-chip marker and Aimosti reads it from the file you already have. Rarer NUDT15 alleles are not on the chip, and an unresolved genotype is reported as such.
My TPMT test came back normal. Do I still need to think about NUDT15?
Yes, and that is the whole point of this gene. TPMT and NUDT15 act at different steps, so a normal result for one says nothing about the other. CPIC grades both in the same guideline for that reason.
Does ancestry change how much this matters?
It changes the prior probability, not the interpretation. Reduced-function NUDT15 alleles are more common in East Asian and Hispanic populations, so testing has more yield there. If you carry one, the guidance is the same wherever your ancestry lies.
Is this a substitute for the test my clinic would order?
No. If a thiopurine is being started, the prescriber should order the clinical test. A result read from your own file is useful context and a reason to ask the question, not a clinical result.