title: 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.
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany. selinski@ifado.de
authors.forename: Silvia
authors.initials: S
authors.lastname: Selinski
authors.forename: Meinolf
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authors.lastname: Blaszkewicz
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Lehmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Ovsiannikov
authors.forename: Oliver
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authors.forename: Christoph
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authors.lastname: Guballa
authors.forename: Alexander
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authors.lastname: Kress
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authors.forename: Holger
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authors.lastname: Gerullis
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authors.forename: Dimitri
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authors.lastname: Barski
authors.forename: Günter
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authors.lastname: Niegisch
authors.forename: Peter
authors.initials: P
authors.lastname: Albers
authors.forename: Sebastian
authors.initials: S
authors.lastname: Frees
authors.forename: Walburgis
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authors.forename: Joachim W
authors.initials: JW
authors.lastname: Thüroff
authors.forename: Miriam
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authors.lastname: Angeli-Greaves
authors.forename: Thilo
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authors.lastname: Seidel
authors.forename: Gerhard
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authors.lastname: Roth
authors.forename: Holger
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authors.lastname: Dietrich
authors.forename: Rainer
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authors.lastname: Ebbinghaus
authors.forename: Hans M
authors.initials: HM
authors.lastname: Prager
authors.forename: Hermann M
authors.initials: HM
authors.lastname: Bolt
authors.forename: Michael
authors.initials: M
authors.lastname: Falkenstein
authors.forename: Anna
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Torsten
authors.initials: T
authors.lastname: Klein
authors.forename: Thomas
authors.initials: T
authors.lastname: Reckwitz
authors.forename: Hermann C
authors.initials: HC
authors.lastname: Roemer
authors.forename: Dietrich
authors.initials: D
authors.lastname: Löhlein
authors.forename: Wobbeke
authors.initials: W
authors.lastname: Weistenhöfer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schöps
authors.forename: Syed Adibul
authors.initials: SA
authors.lastname: Hassan Rizvi
authors.forename: Muhammad
authors.initials: M
authors.lastname: Aslam
authors.forename: Gergely
authors.initials: G
authors.lastname: Bánfi
authors.forename: Imre
authors.initials: I
authors.lastname: Romics
authors.forename: Michael
authors.initials: M
authors.lastname: Steffens
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.forename: Andreas
authors.initials: A
authors.lastname: Winterpacht
authors.forename: Katja
authors.initials: K
authors.lastname: Ickstadt
authors.forename: Holger
authors.initials: H
authors.lastname: Schwender
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.forename: Klaus
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authors.lastname: Golka
mesh_terms: D000107:Acetylation; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D002110:Caffeine / Q000494:pharmacology*; D016022:Case-Control Studies; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005838:Genotype; D060005:Genotyping Techniques / Q000379:methods; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012680:Sensitivity and Specificity
chemical_list: D002110:Caffeine; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human