Unraveling ambiguous NAT2 genotyping data.
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.
Agúndez
José A G
JA
Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain. jagundez@unex.es
Golka
Klaus
K
Martínez
Carmen
C
Selinski
Silvia
S
Blaszkewicz
Meinolf
M
García-Martín
Elena
E
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
D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human