Identification and characterization of novel sequence variations in the cytochrome P4502D6 ( ) gene in African Americans

• Published in: The pharmacogenomics journal Vol. 5; no. 3; pp. 173 - 182
• Main Authors: Gaedigk, A, Bhathena, A, Ndjountché, L, Pearce, R E, Abdel-Rahman, S M, Alander, S W, Bradford, L DiAnne, Rogan, P K, Leeder, J Steven
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-01-2005
• Subjects: African Americans; Alleles; Cloning, Molecular; CYP2D6 protein; Cytochrome; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P450; Dextromethorphan - pharmacokinetics; Discordance; Ethanolamines - pharmacokinetics; Female; Gene deletion; Gene Expression; Gene Frequency; Genes, Reporter - genetics; Genetic Variation; Genotype; Genotype & phenotype; Genotypes; Genotyping; Haplotypes; Humans; Liver - embryology; Liver - enzymology; Luciferases - genetics; Phenotype; Phenotypes; Polymorphism, Single Nucleotide - genetics; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; RNA - biosynthesis; RNA Splicing - genetics; Single-nucleotide polymorphism; Tramadol - pharmacokinetics; Transcription; Transcription, Genetic
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/sj.tpj.6500305

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.