rs1208 — NAT2 R268K

NAT2 R268K - The Acetylation Tag SNP

The R268K variant (rs1208) is often used as a tag SNP for NAT2 acetylator status because it is in strong linkage disequilibrium ¹¹ Linkage disequilibrium means nearby genetic variants tend to be inherited together as a block rather than independently with rapid acetylator haplotypes. The A allele at this position tags the NAT2*4 rapid acetylator haplotype, which is the ancestral (wild-type) form of the enzyme with full activity.

Understanding Tag SNPs

A tag SNP is a genetic variant that can serve as a proxy for a larger haplotype block. ²² A haplotype block is a set of nearby variants on the same chromosome that are almost always inherited together In the case of rs1208, the A allele reliably indicates the presence of a rapid acetylator allele, while the G allele indicates a slow acetylator allele. This makes it useful for genotyping studies where testing all NAT2 variants is not practical. Notably, the G allele is very rare in East Asian populations (~4%) but common in Europeans (~43%) and Africans (~41%).

The Bigger Picture

Your NAT2 acetylator phenotype - rapid, intermediate, or slow - has practical consequences for both environmental exposures and medication responses. Slow acetylators clear certain carcinogens (particularly aromatic amines from cigarette smoke and heterocyclic amines from cooked meat) more slowly, allowing these compounds to interact with DNA for longer periods.

Metabolic Associations

Beyond detoxification, rs1208 was identified as the lead SNP in a genome-wide association study³³ genome-wide association study
Knowles JW et al. Identification and validation of NAT2 as an insulin sensitivity gene. J Clin Invest, 2015 linking NAT2 to insulin sensitivity. The slow acetylator genotype was associated with decreased insulin sensitivity independent of BMI, and nominally associated with increased fasting glucose, HbA1c, total and LDL cholesterol, triglycerides, and coronary artery disease risk.

Balancing Risks

Interestingly, slow acetylation is not universally bad. While slow acetylators have higher bladder cancer risk from smoking, rapid acetylators have higher colorectal cancer risk from well-done meat. This is because NAT2 can both activate and deactivate different carcinogens depending on the substrate. ⁴⁴ NAT2 can either detoxify a carcinogen or convert a pro-carcinogen into its active, DNA-damaging form The practical takeaway is universal: minimize exposure to both cigarette smoke and heavily charred meats regardless of your acetylator status.