Thiopurine metabolism (TPMT and NUDT15 genes)

Thiopurine drugs such as azathioprine are handled by two genes, TPMT and NUDT15. Doctors combine both into one dosing recommendation, driven by whichever shows more reduced function.

Why two genes are read together

Thiopurines, meaning azathioprine, mercaptopurine and thioguanine, are used in inflammatory bowel disease, autoimmune conditions and leukaemia. They are converted into active metabolites that interfere with DNA synthesis, and two separate enzymes limit how much active drug accumulates. TPMT diverts the drug down an inactive path, and NUDT15 breaks down the active metabolite before it reaches DNA.

Reduced function in either enzyme lets active metabolites build up in bone marrow, where the consequence is myelosuppression: blood counts fall, sometimes severely and occasionally fatally. Reading only one gene misses half of the people at risk, which is why this panel reads both.

NUDT15 is why the second gene exists on this page

TPMT testing became standard in the 1990s, mostly on European-ancestry evidence, and it left a puzzle: many East Asian patients suffered severe thiopurine toxicity with normal TPMT. NUDT15 was identified in 2014 as the missing explanation.

The frequencies explain the history. The NUDT15 variant read here is carried by roughly one in ten people of East Asian ancestry and is rare in European-ancestry populations, while TPMT deficiency shows the opposite pattern. A test built in one population had a blind spot in another, and this is one of the clearest examples of that problem being found and fixed.

How strong the evidence is

CPIC rates the thiopurine guidance level A, one of the strongest categories, and recommends substantially reduced starting doses for intermediate metabolizers and either drastic reduction or an alternative drug for poor metabolizers. Pre-treatment testing for both genes is recommended before starting thiopurines and is increasingly routine.

This is, alongside DPYD and abacavir, one of the few results on this site where genotype changes a prescribing decision rather than refining a probability.

What this panel does not cover

It reads the common reduced-function versions: TPMT *2 and *3C, and NUDT15 *3. Rarer reduced-function alleles in both genes exist and are not read, so a normal result does not fully exclude reduced metabolism. The TPMT variant read here also cannot distinguish *3A, the most common European deficiency haplotype, from *3C alone, though both carry reduced function.

Regular blood count monitoring is standard on thiopurines regardless of genotype, precisely because genetics explains part of the risk rather than all of it. Bone marrow suppression can also arise from infection, interacting drugs such as allopurinol, and kidney or liver impairment.

What each TPMT + NUDT15 result means

Normal thiopurine metabolism. You don't carry the tested reduced-function TPMT or NUDT15 variants, so from what these genes show you break down thiopurine medications normally.

Reduced thiopurine metabolism. You carry one reduced-function copy in TPMT or NUDT15, so thiopurine drugs hit you harder. If prescribed, a lower starting dose is usually recommended to avoid a dangerous drop in blood counts.

Poor thiopurine metabolism. One of your thiopurine genes (TPMT or NUDT15) has two reduced-function copies, so standard thiopurine doses can cause severe drops in blood cells. Doctors usually avoid these drugs or use much lower doses for this genotype.

Evidence & sources

This panel reads TPMT*3C (rs1142345), TPMT*2 (rs1800462) and NUDT15*3 (rs116855232).

Reads the most common reduced-function versions of TPMT and NUDT15. Some rarer reduced versions of these genes are not tested, so a 'normal' result does not fully exclude reduced metabolism.

CPIC provides dosing guidance for azathioprine based on this gene.

Common questions

Should I be tested before starting azathioprine? Guidelines recommend testing both TPMT and NUDT15 before starting thiopurines, and it is increasingly routine practice. That is a clinical test through your prescriber, not a consumer result, though a consumer result showing a reduced-function variant is worth mentioning so the clinical test is not skipped.

Why does my TPMT result matter if I am East Asian? It matters less than NUDT15 does. Thiopurine intolerance in East Asian populations is driven substantially by NUDT15, which is carried by roughly one in ten people of East Asian ancestry, while TPMT deficiency is comparatively rare there. Both are read here for exactly that reason.

Related

Abacavir hypersensitivity (HLA-B*57:01) · CYP2C19 metabolizer status (clopidogrel & others) · Drug acetylation speed (NAT2) · Fluoropyrimidine (5-FU) toxicity risk · Hepatitis C treatment response (IL28B) · Opioid receptor response (OPRM1 A118G) · Warfarin dose sensitivity