View source for 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 [[Phenotype:NUDT15 poor metabolizer|poor metabolizer]] and [[Phenotype:NUDT15 intermediate metabolizer|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|azathioprine]], [[Mercaptopurine|mercaptopurine]], and [[Thioguanine|thioguanine]] applies, and NUDT15 genotype gives no reason to reduce the starting dose.<ref name="relling2019">Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. ''Clinical Pharmacology and Therapeutics''. 2019 May;105(5):1095-1105. PMID: 30447069.</ref>

The essential caveat is the converse of the one stated on the [[Phenotype:TPMT normal metabolizer|TPMT normal metabolizer]] page. A normal ''NUDT15'' result does not, on its own, clear a patient for standard thiopurine dosing, because the parallel gene [[Enzyme:TPMT|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|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]]

== References ==

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[[Category:Pharmacogenomic phenotypes]]