rs1495741: NAT2, acetylation of urinary and blood metabolites, and bladder cancer

posted in: Genetic associations

We first reported an association of the NAT2 in a GWAS with NMR-derived urinary metabolites in [Suhre et al., Nature Genetics, 2011]:

“On chromosome 8, SNP rs4921914 is located 14 kb downstream of and in linkage disequilibrium with the gene encoding N-acetyltransferase-2 (NAT2). The strongest metabolic trait associated with this locus in our study is the ratio between formate and succinate concentrations. NAT2 is a key enzyme in the conjugation of certain drugs and other xenobiotics with various hydrazine or arylamine structures and is able to bioactivate several known carcinogens. Polymorphisms in the NAT2 locus are associated with toxicities to docetaxel and thalidomide treatment, and a recent GWAS linked NAT2 to triglyceride levels and coronary artery disease. NAT2 polymorphisms segregate the human population into rapid, intermediate and slow acetylators and are associated with higher incidences of cancer and drug toxicity.”

Rueedi et al. [PLoS Genetics, 2014] replicated the rs4921914 association with NMR features in urine.

Suhre et al. [Nature, 2011] reported an association of rs1495743 with 1-methylxanthine/4-acetamidobutanoate ratios in blood. Shin et al. [Nature Genetics, 2014] replicated this association [details].

We recently observed a strong association of NAT2 SNP rs1495741 with 5-Acetylamino-6-formylamino-3-methyluracil in urine [unpublished]. This metabolite is a direct product of the arylamine N-acetyltransferase NAT2 [EC:] [HMDB].

Genetic variance in NAT2 is also associated with slow acetylation and the risk of bladder cancer [paper].

Interaction of the NAT2 tag SNP (rs1495741) with cigarette smoking in bladder cancer risk has been observed [data] [paper].

The NAT2 tag SNP rs1495741 correlates with the susceptibility of antituberculosis drug-induced hepatotoxicity [pubmed].