A Four-SNP NAT2 Genotyping Panel Recommended to Infer Human Acetylator Phenotype

Abstract

A four-SNP NAT2 genotyping panel recommended to infer human acetylator phenotype We thank Suarez-Kurtz and colleagues for their Letter to the Editor [1] providing confirmation and expansion of the conclusions outlined in our paper recently published in Pharmacogenomics [2]. As described in our paper, we assessed the accuracy of NAT2 SNP genotyping panels to confer acetylator phenotype in cryopreserved human hepatocytes derived from a convenience sample of individuals in the USA with ethnic frequency similar to the 2010 US population census [2]. A major strength of our published study [2] is the experimental measurement of acetylator phenotype whereas a major strength of the Suarez-Kurtz et al. study [1] is an increased ethnic diversity of the sample set, including high percentages of African, Asian, Amerindian and admixed populations.Although our study [2] measured acetylator phenotype experimentally and the Suarez-Kurtz et al. study [1] inferred acetylator phenotype, nevertheless the results and conclusions of the two studies are complementary. The overall conclusion from our published paper was that a NAT2 4-SNP genotype panel consisting of rs1801279 (191G>A), rs1801280 (341T>C), rs1799930 (590G>A) and rs1799931 (857G>A) infers NAT2 acetylator phenotype with high (experimentally determined as 98.4%) accuracy, and is recommended over the tagSNP, 2-SNP, 3-SNP (and, for economy of scale, the 7-SNP) genotyping panels, particularly in populations of non-European ancestry [2]. Suarez-Kurtz et al. conclude that 'collectively, the present ana lysis verified in Asian (Japanese), African (Mozambican), native-American (Guarani) andadmixed Brazilian cohorts that this same 4-SNP genotype panel may be used, with economy of scale, to infer with 100% accuracy the NAT2 acetylator phenotype [1]. The difference in 98.4 versus 100% accuracy is explained by the fact that NAT2 acetylator phenotype was determined experimentally in our published paper [2], whereas 100% accuracy is based on inference of acetylator phenotype in the Suarez-Kurtz et al. paper [1]. Both studies also found lower accuracy with alternative NAT2 SNP genotype panels.In conclusion, our two studies are complimentary and we appreciate the opportunity to comment on these findings.

PharmGKB summary

“…Now, many studies genotype NAT2 variants to define acetylator phenotype instead, and the SNPs investigated can vary between studies. An economic 4-SNP genotyping panel was reported to accurately predict NAT2 acetylator phenotype in different populations; rs1801280, rs1799930, rs1799931 and rs1801279 (Table 1) [40–42]. Early genotyping methods based on PCR-RFLP typically used Kpn I (cuts wildtype allele C at position 481 rs1799929), Taq 1 (cuts wildtype allele G at position 590 rs1799930) and BamH I (cuts wildtype allele G at position 857 rs1799931) enzymes to distinguish NAT2 * 4 from the slow alleles described as *5 , *6 and *7 , respectively (for example [43, 44]) or defined as *5B , *6A , and *7B , respectively (for example [45, 46]).…”