Accuracy of Various Human NAT2 SNP Genotyping Panels to Infer Rapid, Intermediate and Slow Acetylator Phenotypes

Abstract

Aim Humans exhibit genetic polymorphism in NAT2 resulting in rapid, intermediate and slow acetylator phenotypes. Over 65 NAT2 variants possessing one or more SNPs in the 870-bp NAT2 coding region have been reported. The seven most frequent SNPs are rs1801279 (191G>A), rs1041983 (282C>T), rs1801280 (341T>C), rs1799929 (481C>T), rs1799930 (590G>A), rs1208 (803A>G) and rs1799931 (857G>A). The majority of studies investigate the NAT2 genotype assay for three SNPs: 481C>T, 590G>A and 857G>A. A tag-SNP (rs1495741) recently identified in a genome-wide association study has also been proposed as a biomarker for the NAT2 phenotype. Materials & methods Sulfamethazine N-acetyltransferase catalytic activities were measured in cryopreserved human hepatocytes from a convenience sample of individuals in the USA with an ethnic frequency similar to the 2010 US population census. These activities were segregated by the tag-SNP rs1495741 and each of the seven SNPs described above. We assessed the accuracy of the tag-SNP and various two-, three-, four- and seven-SNP genotyping panels for their ability to accurately infer NAT2 phenotype. Results The accuracy of the various NAT2 SNP genotype panels to infer NAT2 phenotype were as follows: seven-SNP: 98.4%; tag-SNP: 77.7%; two-SNP: 96.1%; three-SNP: 92.2%; and four-SNP: 98.4%. Conclusion A NAT2 four-SNP genotype panel of rs1801279 (191G>A), rs1801280 (341T>C), rs1799930 (590G>A) and rs1799931 (857G>A) infers NAT2 acetylator phenotype with high accuracy, and is recommended over the tag-, two-, three- and (for economy of scale) the seven-SNP genotyping panels, particularly in populations of non-European ancestry.

Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene

“…edu/medicine/departments/pharmacology/news-information/ nat). However, humans can be classified into "rapid," "intermediate," or "slow" acetylators of isoniazid or sulfamethazine (the canonical substrates) on the basis of the haplotype structure that can be inferred with great accuracy in European populations from a subset of the 7 more common coding SNPs (22,23). To assess whether the association that we observed with insulin sensitivity was being driven by predicted acetylator status, we used a 6-SNP mental Table 2).…”

Sequence analysis of theN-acetyltransferase 2 gene (NAT2) among Jordanian volunteers

“…Some volunteers were found to carry only the 481C>T but not the 341T>C variant on the NAT2 gene, which indicates that those volunteers were considered genetically as fast acetylators. Therefore, detection of 481C>T variant as a representative SNP of NAT2*5 allele among Jordanians may give a false-slow encoding NAT2 genotype and can overestimate the prevalence of slow acetylator phenotypes among Jordanians [35]. Therefore, genotyping the slow allele NAT2*5 using the 481C>T variant among Jordanian population is not recommended.…”

Mathematical model to predict methotrexate elimination in children with acute lymphoblastic leukemia

“…Slow acetylators have mutations in both allele of the gene and have a very slow metabolism capacity, thus being exposed to severe adverse effects because of prolonged exposure to high serum MTX values. In these patients, doses should be reduced by 20-50% and two or more drugs using the same elimination pathway should not be administered (35). Intermediate acetylators are heterozygote patients, who may receive the respective compounds in small doses, with the same precautions.…”