Phenotype:NUDT15 normal metabolizer

A NUDT15 normal metabolizer (NM) is a person who carries two normal-function NUDT15 alleles and therefore has the typical, reference level of NUDT15 enzyme activity. It is one of the three metabolizer phenotypes assigned from NUDT15 genotype, above the poor metabolizer and intermediate metabolizer. NUDT15 has no rapid or ultrarapid phenotype, so the normal metabolizer is the highest-activity phenotype on the scale. This page describes the normal-metabolizer phenotype; the enzyme itself is covered at Enzyme:NUDT15.

The normal metabolizer is the reference phenotype. The standard doses of the thiopurine medicines are calibrated to normal-metabolizer patients, and for a NUDT15 normal metabolizer, NUDT15 genotype is not a reason to depart from standard thiopurine dosing.

Genotype basis

The normal-metabolizer phenotype is produced by the \*1/\*1 diplotype, two normal-function alleles. The full allele catalogue is described on the Enzyme:NUDT15 page.

Population frequency

The NUDT15 normal-metabolizer phenotype is the majority phenotype in every population, and the great majority in European-ancestry and African-ancestry populations, where the loss-of-function \*3 allele is rare. It is still the majority phenotype in East Asian, Hispanic, Latino, and South Asian populations, but less overwhelmingly so, because the higher \*3 frequency in those populations gives the intermediate- and poor-metabolizer phenotypes a larger share.

Clinical significance

For a NUDT15 normal metabolizer, standard dosing of azathioprine, mercaptopurine, and thioguanine applies, and NUDT15 genotype gives no reason to reduce the starting dose.

The essential caveat is the converse of the one stated on the TPMT normal metabolizer page. A normal NUDT15 result does not, on its own, clear a patient for standard thiopurine dosing, because the parallel gene TPMT produces the same thiopurine-myelosuppression phenotype and its loss-of-function alleles are common in exactly the populations where NUDT15 loss-of-function is rare. A NUDT15 normal metabolizer may still be a TPMT poor or intermediate metabolizer. The two genes must be tested together; a normal result for either one is reassurance about half of the thiopurine-safety picture, not all of it.

Standard thiopurine monitoring with periodic blood counts remains appropriate, because non-genetic factors, including the allopurinol interaction, can still produce thiopurine toxicity in a normal metabolizer.

See also

• Enzyme:NUDT15, the enzyme, its history, and the guardian-enzyme explanation in full.
• Phenotype:NUDT15 poor metabolizer, Phenotype:NUDT15 intermediate metabolizer, the sibling phenotypes.
• Enzyme:TPMT and Phenotype:TPMT normal metabolizer, the parallel thiopurine-safety gene that a normal NUDT15 result does not cover.
• Azathioprine, Mercaptopurine, Thioguanine (the entire clinical NUDT15 substrate set).
• Category:Pharmacogenomic phenotypes