title: Unraveling ambiguous NAT2 genotyping data.
abstract: BACKGROUND
  Arylamine N-acetyltransferase 2 (CoASAc; NAT2, EC 2.3.1.5) is a drug-metabolizing enzyme that displays common polymorphisms leading to impaired drug metabolism and adverse drug effects. Determination of the N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2) genotype in clinical practice is hampered by the occurrence of ambiguous haplotype combinations that may lead to patient misclassification. We determined the frequencies for ambiguous NAT2 haplotypes and diplotypes in a white population and investigated the use of PHASE v2.1.1, a statistical program for haplotype reconstruction, to clarify this ambiguity and classify individuals according to their acetylation status.
  
  
  METHODS
  By means of allele-specific haplotype mapping and sequencing, we determined the haplotypes for 7 common single-nucleotide polymorphisms in the NAT2 gene (n = 2624 haplotypes). To test the performance of PHASE, actual genotypes were deconstructed and then reconstructed by haplotype prediction.
  
  
  RESULTS
  We identified 21 NAT2 allelic variants, including a new variant allele that combines the single-nucleotide polymorphisms rs1801279, rs1799929, and rs1208. In contrast, the previously described variant alleles *5G, *5J, *6E, *7A, *11A, *11B, and *14B were not identified in the study population. Ambiguous haplotypes were observed in 98 alleles (3.7%), and ambiguous diplotypes were observed in 64 individuals (4.9%). Eleven individuals (0.8%) were misclassified by the use of haplotype prediction.
  
  
  CONCLUSIONS
  Ambiguous NAT2 genotyping data are common. Actual NAT2 genotypes cannot be fully determined by haplotype prediction techniques. This study provides real haplotype data that can be used as a guide to convert NAT2 haplotypes and diplotypes into actual genotypes in white individuals.
authors.affiliation: Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain. jagundez@unex.es
authors.forename: José A G
authors.initials: JA
authors.lastname: Agúndez
authors.forename: Klaus
authors.initials: K
authors.lastname: Golka
authors.forename: Carmen
authors.initials: C
authors.lastname: Martínez
authors.forename: Silvia
authors.initials: S
authors.lastname: Selinski
authors.forename: Meinolf
authors.initials: M
authors.lastname: Blaszkewicz
authors.forename: Elena
authors.initials: E
authors.lastname: García-Martín
mesh_terms: D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D019295:Computational Biology / Q000379:methods / Q000706:statistics & numerical data; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044465:White People
chemical_list: D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human