PIII-53Discordance between slow acetylator phenotype and genotype for N-acetyltransferase 2 (NAT-2) in a Hmong population

Abstract

BACKGROUND Polymorphisms of NAT-2 acetylation contribute to drug toxicity, efficacy and cancer risk. Predominance of slow acetylation (SA) phenotype in ethnically distinct populations may have clinical implications for drug selection and cancer risk. The purpose of this study was to determine the genetic basis of SA phenotype predominance in Minnesota Hmong. METHODS Urine and DNA were obtained for phenotype and genotype analysis from unrelated healthy Hmong 18 and 65 years of age. Urinary molar ratios (MR) of caffeine metabolites (AFMU/1X) identified rapid acetylators (RA) phenotypes with a MR >= 0.6 and SA with MR < 0.6. Direct sequencing of the NAT-2 coding-region followed by cloning techniques for ambiguous genotypes identified individuals homozygous or heterozygous with a *4 and *13 allele as RA and variants as SA by genotype. RESULTS From 61 subjects (30±11 years, 27 male), analysis of 51 urine-DNA pairs identified 46 (90.2%) SA and 5 (9.8%) RA by phenotype. In contrast, genotypic analysis identified 5 (9.8%) SA and 46 (90.2%) RA. An 84% discordance between phenotype and genotype was observed. Direct sequencing did not reveal novel NAT-2 polymorphisms. CONCLUSIONS Genotypic analysis appears to demonstrate considerable discordance with the phenotype in Hmong. Genotyping alone, without a metabolic probe, would not have accurately predicted acetylation phenotype. Clinical Pharmacology & Therapeutics (2005) 79, P72–P72; doi: 10.1016/j.clpt.2005.12.261