rs1799930 — NAT2 R197Q

NAT2 R197Q - The Second Acetylation Determinant

The R197Q variant (rs1799930) is another common slow acetylator allele in the NAT2 gene. It changes arginine to glutamine at position 197 of the enzyme, affecting protein stability and catalytic activity. This variant characterizes the NAT2*6A haplotype.

The Mechanism

Arginine at position 197 forms important salt bridges ¹¹ Salt bridges are electrostatic bonds between oppositely charged amino acids that help hold a protein's 3D shape together that stabilize the NAT2 protein structure. Replacing it with glutamine (A allele) disrupts these interactions, making the enzyme less stable and more prone to degradation. The result is lower steady-state enzyme levels and slower acetylation capacity.

Determining Your Acetylator Status

Your overall NAT2 acetylator phenotype ²² Your acetylator phenotype is how fast you actually metabolize NAT2 substrates, determined by which combination of alleles you inherited depends on the combination of all three major variants: rs1801280 (I114T), rs1799930 (R197Q), and rs1208 (R268K). Having two slow alleles at any combination of these positions makes you a slow acetylator. Having one slow and one rapid allele makes you intermediate, and having no slow alleles makes you a rapid acetylator.

Population Genetics

The frequency of slow acetylator alleles varies dramatically across populations. About 50-60% of Europeans and Africans are slow acetylators, while only about 10-20% of East Asians are. This variation likely reflects different dietary and environmental selective pressures throughout human history. Unlike I114T (rs1801280) which is very rare in East Asians, R197Q has a more uniform global distribution (~23-36% across populations).

Drug Implications

NAT2 status affects the metabolism of several medications beyond isoniazid. Sulfasalazine (for inflammatory bowel disease), hydralazine (for hypertension), and procainamide (for arrhythmias) are all NAT2 substrates. ³³ These drugs are rarely used today in general practice, but isoniazid remains a frontline tuberculosis treatment worldwide Slow acetylators may experience more side effects from these drugs at standard doses.

Metabolic Associations

Recent research has also identified NAT2 as an insulin sensitivity gene⁴⁴ insulin sensitivity gene
Knowles JW et al. Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene. J Clin Invest, 2015, with slow acetylator status associated with decreased insulin sensitivity independent of BMI. This adds a metabolic dimension to NAT2 pharmacogenomics.