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Received for publication November 10, 2005.
Revised January 11, 2006.
Accepted for publication January 12, 2006.
Unexplained cases of CYP2D6 genotype/phenotype discordance continue to be discovered. In previous studies several African Americans with a poor metabolizer phenotype carried the reduced function CYP2D6*10 allele in combination with a nonfunctional allele. We pursued the possibility that these alleles harbor either a known sequence variation (i.e. CYP2D6*36 carrying a gene conversion in exon 9 along the CYP2D6*10-defining 100C>T SNP) or novel sequences variation(s). Discordant cases were evaluated by long-range PCR to test for gene rearrangement events and a 6.6 kb PCR product encompassing the CYP2D6 gene was cloned and entirely sequenced. Subsequently, allele frequencies were determined in different study populations comprising Caucasians, African Americans and Asians. Analyses covering the CYP2D7-2D6 gene region established that CYP2D6*36 did not only exist as a gene duplication (CYP2D6*36x2) or in tandem with *10 (CYP2D6*36+*10), as previously reported, but also by itself. This 'single' CYP2D6*36 allele was found in nine African Americans and one Asian, but was absent in the Caucasians tested. Ultimately, the presence of CYP2D6*36 resolved genotype/phenotype discordance in three cases. We also discovered an exon 9 conversion-positive CYP2D6*4 gene in a duplication arrangement (CYP2D6*4Nx2) and a CYP2D6*4 allele lacking 100C>T (CYP2D6*4M) in two Caucasian subjects. The discovery of an allele that carries only one CYP2D6*36 gene copy provides unequivocal evidence that both, CYP2D6*36 and *36x2 are associated with a poor metabolizer phenotype. Given a combined frequency of between 0.5-3% in African Americans and Asians genotyping for CYP2D6*36 should improve the accuracy of genotype-based phenotype prediction in these populations.
Key words:
CYP2D, cytochrome P450, cytochrome P450 function, genetic polymorphism, genotype, human CYP enzymes, pharmacogenetics, polymorphisms
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