1. ¹Division of Clinical Pharmacology and Experimental Therapeutics, Children's Mercy Hospital & Clinics, Kansas City, MO, USA
2. ²Morehouse School of Medicine, Atlanta, GA, USA

Correspondence: Dr A Gaedigk, Division of Clinical Pharmacology & Experimental Therapeutics, Children's Mercy Hospital & Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA. Tel: +1 816 234 3941; Fax: +1 816 855 1958; E-mail: agaedigk@cmh.edu

Received 25 August 2004; Revised 13 December 2004; Accepted 10 January 2005; Published online 15 March 2005.

Abstract

Cytochrome P4502D6 (CYP2D6) genotyping reliably predicts poor metabolizer phenotype in Caucasians, but is less accurate in African Americans. To evaluate discordance we have observed in phenotype to genotype correlation studies, select African American subjects were chosen for complete resequencing of the CYP2D6 gene including 4.2 kb of the CYP2D7-2D6 intergenic region. Comparisons were made to a CYP2D6^*1 reference sequence revealing novel SNPs in the upstream, coding and intervening sequences. These sequence variations, defining four functional alleles (CYP2D6^*41B, ^*45A and B and ^*46), were characterized for their ability to influence splice site strength, transcription level or catalytic protein activity. Furthermore, their frequency was determined in a population of 251 African Americans. A -692_TGTG deletion (CYP2D6^*45B) did not significantly decrease gene expression, nor could any other upstream SNP explain a genotype-discordant case. CYP2D6^*45 and ^*46 have a combined frequency of 4% and can be identified by a common SNP. Carriers are predicted to exhibit an extensive or intermediate CYP2D6 phenotype.