Phenotype:NUDT15 poor metabolizer

A NUDT15 poor metabolizer (PM) is a person who carries two no-function or decreased-function NUDT15 alleles and therefore has little or no functional NUDT15 enzyme activity. It is one of the three metabolizer phenotypes assigned from NUDT15 genotype, the others being the intermediate metabolizer and the normal metabolizer. NUDT15 has no rapid or ultrarapid phenotype. This page describes the poor-metabolizer phenotype; the enzyme itself is covered at Enzyme:NUDT15.

The clinical stake is the same as for the TPMT poor metabolizer, and just as stark: a NUDT15 poor metabolizer given a standard dose of a thiopurine medicine is at high risk of severe, potentially fatal bone-marrow suppression. The mechanism is the guardian-enzyme logic set out on the enzyme page. NUDT15 dephosphorylates the active thioguanine triphosphate metabolites of a thiopurine before they can be incorporated into DNA. When NUDT15 activity is absent, more of that active metabolite survives to be built into DNA, DNA damage rises, and the bone marrow is the tissue that suffers. As with TPMT, the danger comes from the loss of a protective step, not from a failure to activate a medicine.

Genotype basis

The poor-metabolizer phenotype is produced by a NUDT15 diplotype combining two no-function or decreased-function alleles. The dominant allele is:

• \*3 (rs116855232, Arg139Cys), by far the most important NUDT15 loss-of-function allele worldwide, and the variant identified in the original 2014 association study.

Diplotypes such as \*3/\*3, and pairings of \*3 with the rarer \*2 or other reduced-function alleles, produce the poor-metabolizer phenotype. The full allele catalogue is described on the Enzyme:NUDT15 page.

Population frequency

The defining feature of NUDT15 population genetics is its ancestry distribution. The \*3 allele reaches an allele frequency of roughly 10% in East Asian populations and is also common in Hispanic and Latino populations and in South Asian populations, while it is rare in European-ancestry populations (on the order of 0.2%) and rare in African-ancestry populations. The NUDT15 poor-metabolizer phenotype is therefore concentrated in East Asian, Hispanic, Latino, and South Asian patients, very nearly the 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 poor metabolizer receive a drastically reduced thiopurine dose, on the order of 10% of the standard dose, or that a non-thiopurine alternative be selected. Standard dosing in a NUDT15 poor metabolizer risks fatal myelosuppression.

The decisive practical point: a NUDT15 poor metabolizer can have an entirely normal TPMT genotype and normal TPMT activity. For decades, when TPMT was the only thiopurine-safety test, these patients, disproportionately of East Asian ancestry, suffered severe thiopurine myelosuppression that TPMT testing was structurally incapable of predicting. That gap is the reason NUDT15 and TPMT must be tested together, and the reason the CPIC guideline now covers both genes jointly.

See also

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