NAT2: the slow acetylator gene, and what it changes
Slow acetylator status is one of the oldest observations in pharmacogenetics, made in the 1950s from isoniazid side effects, and for most of the intervening seventy years it was a fact in search of an action. The hydralazine guidance is the first place it became a dose.
Also known as: N-acetyltransferase 2, arylamine N-acetyltransferase 2.
What NAT2 does
The enzyme attaches an acetyl group to certain drugs, which is a way of packaging them for disposal. People fall into groups by how quickly they do it, and the split is unusually clean: a slow acetylator clears these drugs at a fraction of the rate of a rapid one from the same dose. Slow acetylation is common everywhere, and the balance between the slow and rapid groups shifts substantially between populations, which is one reason a fixed dose of an acetylated drug has behaved differently in studies run in different places.
The acetylator groups
CPIC grades NAT2 as poor, intermediate or rapid metabolizer, with Indeterminate where the diplotype cannot be graded. Those labels need untangling against the older literature, which describes the same trait as acetylation speed: the poor metabolizer in the table below is the classic slow acetylator, the one who accumulates the drug. The categories come from combinations of a handful of variants that have to be read together as haplotypes, not counted individually.
Medications where it matters
hydralazine (Apresoline)
Hydralazine is a blood-pressure drug, used in heart failure and in pregnancy, and it is cleared by acetylation. A slow acetylator reaches higher levels from the same dose, which means more effect and more of the side effects, including the drug-induced lupus reaction the drug is known for. A rapid acetylator can clear it fast enough that a standard starting dose underdelivers. CPIC's guidance sets different starting and maintenance doses for the two ends, which is a rarer shape than the usual reduce-or-avoid.
| If your result is | Published CPIC guidance |
|---|---|
| Intermediate Metabolizer | Per CPIC (A): "Consider a starting total daily dose of at least 75 mg. Titrate up to 300 mg total daily hydralazine dose as tolerated. NAT2 intermediate metabolizers typically require a 50-100% higher maintenance dose compared to poor metabolizers." |
| Poor Metabolizer | Per CPIC (A): "Initiate therapy at a total daily dose of 40 to 75 mg. Carefully titrate dose upward to clinical effect or guideline-recommended dose; use caution with total daily hydralazine doses of 200 mg or more." |
| Rapid Metabolizer | Per CPIC (A): "Consider a starting total daily dose of at least 75 mg. Titrate up to 300 mg total daily hydralazine dose as tolerated. NAT2 rapid metabolizers typically require a 50-100% higher maintenance dose compared to poor metabolizers." |
Is this in your raw DNA file?
NAT2 is not part of the standard chip or variant-file report. It is a Deep Read gene, read from aligned reads in a BAM or CRAM file. The reason is haplotype structure: the acetylator phenotype depends on which variants sit together on the same chromosome, and a chip that reports each position separately cannot tell a person carrying two variants on one chromosome from a person carrying one on each. Aligned reads can often resolve that. Where they cannot, the result is Indeterminate.
A genotyping chip reads only a few hundred thousand pre-selected positions, about 0.02% of your genome, chosen for common variation. It does not sequence the rest, so it cannot find the rare or novel pathogenic variants the clinical and carrier modules look for: a “no finding” from chip data means “this chip never looked”, far more so than with whole-genome sequencing. Chip data suits common-variant traits, pharmacogenomic tag SNPs, and haplogroup ancestry, not clinical or carrier screening.
Common questions
Is NAT2 in my 23andMe or AncestryDNA raw data?
Individual NAT2 positions are often on the array, but acetylator status depends on how those variants are arranged across the two chromosomes, and a chip cannot see that arrangement. Aimosti reads NAT2 from aligned reads and reports Indeterminate where the haplotypes do not resolve.
I have heard NAT2 matters for isoniazid. Is that in the report?
The association with isoniazid is where this whole field started, and it is well documented. Aimosti's Deep Read restates the CPIC hydralazine guidance for this gene, which is what the table above shows, because that is the guidance CPIC has published. Tuberculosis treatment is managed by a specialist service and is not a place for self-directed adjustment.
Does slow acetylator status affect cancer risk?
There is a long research literature pairing NAT2 status with exposures such as tobacco smoke and certain occupational chemicals, and the findings have been mixed. None of it is graded prescribing guidance, so none of it appears in the report. This page stays inside what CPIC publishes.