Phenotype:NUDT15 intermediate metabolizer

A NUDT15 intermediate metabolizer (IM) is a person who carries one normal-function and one no-function or decreased-function NUDT15 allele, and therefore has reduced but not absent NUDT15 enzyme activity. It is one of the three metabolizer phenotypes assigned from NUDT15 genotype, sitting between the poor metabolizer and the normal metabolizer. NUDT15 has no rapid or ultrarapid phenotype. This page describes the intermediate-metabolizer phenotype; the enzyme itself is covered at Enzyme:NUDT15.

The intermediate metabolizer follows the same guardian-enzyme logic as the poor metabolizer, in milder form. With one functioning NUDT15 allele, the enzyme still dephosphorylates a substantial fraction of the active thioguanine triphosphate metabolites before they can be incorporated into DNA, but less than a normal metabolizer would. The intermediate metabolizer therefore carries a meaningful, clinically actionable excess of thiopurine toxicity risk, short of the poor metabolizer.

Genotype basis

The intermediate-metabolizer phenotype is produced by a NUDT15 diplotype that pairs one normal-function allele with one no-function or decreased-function allele, most often a diplotype carrying a single \*3 allele (such as \*1/\*3). The full allele catalogue is described on the Enzyme:NUDT15 page.

Population frequency

Because the \*3 allele reaches an allele frequency of roughly 10% in East Asian populations and is also common in Hispanic, Latino, and South Asian populations, the NUDT15 intermediate-metabolizer phenotype is common in those populations and uncommon in European-ancestry and African-ancestry populations. As with the poor metabolizer, this distribution is the near-mirror image of the TPMT loss-of-function distribution.

Clinical consequences

For the thiopurine medicines azathioprine, mercaptopurine, and thioguanine, the Clinical Pharmacogenetics Implementation Consortium recommends that a NUDT15 intermediate metabolizer start at a reduced thiopurine dose with blood-count monitoring and titration as tolerated, a meaningful reduction but less drastic than the roughly 10% dose advised for the poor metabolizer.

As for the poor metabolizer, the essential practical point is that NUDT15 must be tested alongside TPMT. A NUDT15 intermediate metabolizer can have a fully normal TPMT genotype, and the CPIC guideline provides a joint framework for interpreting the two genes together: a patient who is intermediate for both carries more risk than one who is intermediate for a single gene.

See also

• Enzyme:NUDT15, the enzyme, its history, and the guardian-enzyme explanation in full.
• Phenotype:NUDT15 poor metabolizer, Phenotype:NUDT15 normal metabolizer, the sibling phenotypes.
• Enzyme:TPMT, the parallel thiopurine-safety gene tested jointly with NUDT15.
• Azathioprine, Mercaptopurine, Thioguanine (the entire clinical NUDT15 substrate set).
• Category:Pharmacogenomic phenotypes