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Discordance Between N-acetyltransferase 2 Phenotype and Genotype in a Population of Hmong Subjects

From the Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota (Dr Straka, Dr Burkhardt); the Central Arkansas Veterans Healthcare System, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas (Dr Lang); the Department of Pharmacy, North Memorial Hospital, Robbinsdale, Minnesota (Dr Hadsall); and the Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota (Dr Tsai).

Polymorphisms of N-acetyltransferase 2 (NAT2) acetylation may influence drug toxicities and efficacy and are associated with a differential susceptibility to select cancers. Acetylation phenotype may have clinical implications. The purposes of this study were to determine the genetic basis of an apparent predominance of slow acetylation phenotype and to assess concordance with genotype in a population of Hmong residing in Minnesota. Urine and DNA obtained from unrelated Hmong 18 to 65 years of age were used to determine phenotype from caffeine metabolites, whereas direct nucleotide sequencing of the NAT2 coding region, followed by cloning, identified all known allelic variants. From 61 subjects (27 men, 30 ± 11 years), analysis of 50 urine-DNA pairs identified 46 (92%) slow acetylators and 4 (8%) rapid acetylators by phenotype. Genotypic analysis inferred 5 (10%) slow acetylators and 45 (90%) rapid acetylators. There is 86% discordance between phenotype and genotype. A predominance of NAT2 slow acetylation phenotype in the Hmong is confirmed, and a significant discordance between NAT2 phenotype and genotype is identified. In this population, slow acetylation phenotype determined by a metabolic probe would not have been predicted by genotype alone. Environmental, genetic, or phenotypic anomalies that may contribute to this discordance should be considered and evaluated in future studies within this unique population.

Key Words: N-acetyltransferase 2 • Hmong • phenotype • genotype • caffeine

Address for reprints: Robert J. Straka, PharmD, University of Minnesota, College of Pharmacy, Department of Experimental and Clinical Pharmacology, 7-109 Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455-0353; e-mail: strak001{at}umn.edu.