Clinical Function Assignment of NAT2 Alleles by the Clinical Pharmacogenetics Implementation Consortium Pharmacogene Curation Expert Panel

NAT2 encodes arylamine N-acetyltransferase 2, a phase II enzyme acetylating arylamines and arylhydrazines; NAT2 star alleles modulate this activity and are now assigned standardised clinical function terms (increased, decreased, uncertain, unknown).

NAT2 encodes arylamine N-acetyltransferase 2, a phase II enzyme acetylating arylamines and arylhydrazines including isoniazid, and its extensive polymorphism explains the variable distribution of rapid and slow acetylators across populations. The international, multidisciplinary CPIC NAT2 Pharmacogene Curation Expert Panel (NAT2-PCEP) curated the available in vitro and clinical literature to assess genotype-to-phenotype concordance and the biochemical function of each allele. All 59 star alleles catalogued by PharmVar were assigned a clinical function using CPIC standard terminology: increased function for only two alleles, NAT2 1 and NAT2 4 (historically termed rapid), decreased function for 40 alleles (historically termed slow), uncertain function for 10 and unknown function for seven. The authors stress that harmonising allele function terms and diplotype-to-phenotype assignments is a prerequisite for reliable clinical implementation of NAT2 pharmacogenetic test results.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This paper does not say which dose to prescribe, but it settles the upstream problem that was holding everything else back: until now the slow acetylator label covered heterogeneous realities across laboratories and publications, making studies hard to compare. Moving from the rapid/slow dichotomy to an explicit, allele-by-allele function assignment finally makes NAT2 genotyping reports comparable between centres, and exposes the 17 alleles left with uncertain or unknown function as grey zones still to be documented. For the isoniazid prescriber the dosing translation will come from a future CPIC guideline; for the laboratory professional, this framework applies to report writing as of today.

Analysis by Dr Thibaut Benquey