CYP2D6 poor metabolizer status can be ruled out by a single genotyping assay for the -1584G promoter polymorphism.

Abstract

Accurate prediction of CYP2D6 phenotype from genotype data is important for many clinically relevant drugs. Genotyping strategies targeting allelic variants with diminished or no activity to identify poor metabolizers generally works well in Caucasian (1)(2)(3) and Asian (4)(5) populations, but we have had more limited success (i.e., poor concordance) in African Americans, even after extensive testing (6). For example, genotype analysis predicted poor metabolizer status (by Caucasian-derived antimode definition) in only 4 of 14 individuals, and many individuals predicted to be extensive metabolizers presented as “intermediate” metabolizers (6). A single-nucleotide polymorphism in the CYP2D6 promoter region (−1584G) has been reported to confer higher CYP2D6 activity in vivo than −1584C (7), possibly as a consequence of higher expression of CYP2D6 protein (8). This polymorphism was first associated with CYP2D6*2 alleles, and the CYP nomenclature committee subsequently assigned * 2[−1584G] as CYP2D6 * 2A (and noting that −1584G is probably found on all CYP2D6 * 2 alleles) and * 2[−1584C] as CYP2D6 * 41 , respectively (9). However, −1584G also appears to be linked with the functional CYP2D6 * 35 allele, which has been found in many duplication-negative “ultrarapid” metabolizers (10). For simplicity, we refer to the * 2[−1584G] allele cumulatively as CYP2D6 * 2 because our genotyping procedure does not differentiate among variants CYP2D6 * 2A through K . For reference, −1584G corresponds to −1496G in Ref. (7). The goals of this investigation were ( a ) to explore whether −1584G is exclusively linked to functional allelic variants and hence would allow rapid “positive” identification of extensive metabolizers and reliably rule out poor metabolizer status, and ( b ) to reevaluate the genotype-to-phenotype correlation data in our Caucasian and African-American populations. The use of patients’ DNA samples was approved by the Pediatric Institutional Review Board of Children’s Mercy …