Genotyping NAT2 with only two SNPs (rs1041983 and rs1801280) outperforms the tagging SNP rs1495741 and is equivalent to the conventional 7-SNP NAT2 genotype

Abstract

Genotyping N-acetyltransferase 2 (NAT2) is of high relevance for individualized dosing of antituberculosis drugs and bladder cancer epidemiology. In this study we compared a recently published tagging single nucleotide polymorphism (SNP) (rs1495741) to the conventional 7-SNP genotype (G191A, C282T, T341C, C481T, G590A, A803G and G857A haplotype pairs) and systematically analysed if novel SNP combinations outperform the latter. For this purpose, we studied 3177 individuals by PCR and phenotyped 344 individuals by the caffeine test. Although the tagSNP and the 7-SNP genotype showed a high degree of correlation (R=0.933, P<0.0001) the 7-SNP genotype nevertheless outperformed the tagging SNP with respect to specificity (1.0 vs. 0.9444, P=0.0065). Considering all possible SNP combinations in a receiver operating characteristic analysis we identified a 2-SNP genotype (C282T, T341C) that outperformed the tagging SNP and was equivalent to the 7-SNP genotype. The 2-SNP genotype predicted the correct phenotype with a sensitivity of 0.8643 and a specificity of 1.0. In addition, it predicted the 7-SNP genotype with sensitivity and specificity of 0.9993 and 0.9880, respectively. The prediction of the NAT2 genotype by the 2-SNP genotype performed similar in populations of Caucasian, Venezuelan and Pakistani background. A 2-SNP genotype predicts NAT2 phenotypes with similar sensitivity and specificity as the conventional 7-SNP genotype. This procedure represents a facilitation in individualized dosing of NAT2 substrates without losing sensitivity or specificity.

tagSNP rs1495741 as a useful molecular marker to predict antituberculosis drug-induced hepatotoxicity

“…Usually, combinations of seven single nucleotide polymorphisms (seven-SNP), namely, rs1801279 (G191A), rs1041983 (C282T), rs1801280 (T341C), rs1799929 (C481T), rs1799930 (G590A), rs1208 (A803G), and rs1799931 (G857A), are used to predict the NAT2 acetylation phenotype. However, a recent survey proposed two-SNP (C282T and T341C) as an alternative marker to genotype two-SNPfor inferring NAT2 phenotypes with similar sensibility and specificity as the conventional seven-SNP genotype in Caucasians [10]. Moreover, a recent novel NAT2 tagging SNP, named rs1495741, was found to predict the acetylator profile in populations of European background [10,11].…”

N-acetyltransferase 2 Phenotype, Occupation, and Bladder Cancer Risk: Results from the EPIC Cohort

“…Furthermore, the SNPs selected for genotyping should capture the genetic variation at this locus according to the underlying linkage disequilibrium structure. A good performance has also been shown for a tagging SNP (35,36). The fraction of subjects with slow variants usually increases with an increasing number of SNPs.…”

Human bladder cancer risk calculation based on genome-wide analysis of genetic variants

“…It is well established that slow acetylation (NAT2) and a deletion variant of glutathione S-transferase M1 (GSTM1) are associated with increased bladder cancer risk (Schwender et al 2012;Bell et al 1993;Cartwright et al 1984;Golka et al 1996;Kempkes et al 1996;Hengstler et al 1998). Recently, genome-wide association studies have identified further polymorphisms, and their influence was confirmed in independent case-control series (Kiemeney et al 2008(Kiemeney et al , 2010Rothman et al 2010;Rafnar et al 2009Rafnar et al , 2011Wu et al 2009;Golka et al 2009;Lehmann et al 2010;Selinski et al 2011;Binder et al 2012;Bolt 2012). All the information currently known for the 13 polymorphisms has recently been summarized (Selinski 2012).…”

“…Urinary bladder cancer is the ninth most common cancer worldwide (Roth et al 2012;Golka et al 2011). The strongest known risk factors are cigarette smoking, occupational exposure to bladder carcinogens and male gender (Golka et al 2012a, b;Ovsiannikov et al 2012).…”