The CYP2D6 Activity Score: Translating Genotype Information into a Qualitative Measure of Phenotype

TLDR

Inferring CYP2D6 phenotype from genotype is increasingly difficult because of the expanding number of alleles and their varied activity, complicating translational research and personalized drug therapy. The study aimed to simplify genotype interpretation and enhance phenotype prediction by evaluating an activity‑score (AS) system. Researchers genotyped 25 CYP2D6 variants in 672 mainly Caucasian and African‑American participants and assessed genotype and AS predictive power for dextromethorphan metabolism using linear regression and clustering analyses. Results showed that phenotype prediction was most accurate when ethnicity was included, revealing slower CYP2D6 activity in African Americans with a *2 allele, and indicated that the AS tool merits further prospective evaluation across substrates and populations. Clinical Pharmacology & Therapeutics (2008) doi:10.1038/sj.clpt.6100406.

Abstract

Inferring CYP2D6 phenotype from genotype is increasingly challenging, considering the growing number of alleles and their range of activity. This complexity poses a challenge in translational research where genotyping is being considered as a tool to personalize drug therapy. To simplify genotype interpretation and improve phenotype prediction, we evaluated the utility of an "activity score" (AS) system. Over 25 CYP2D6 allelic variants were genotyped in 672 subjects of primarily Caucasian and African-American heritage. The ability of genotype and AS to accurately predict phenotype using the CYP2D6 probe substrate dextromethorphan was evaluated using linear regression and clustering methods. Phenotype prediction, given as a probability for each AS group, was most accurate if ethnicity was considered; among subjects with genotypes containing a CYP2D6*2 allele, CYP2D6 activity was significantly slower in African Americans compared to Caucasians. The AS tool warrants further prospective evaluation for CYP2D6 substrates and in additional ethnic populations. Clinical Pharmacology & Therapeutics (2008) doi: 10.1038/sj.clpt.6100406