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Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort

An Erratum to this article was published on 21 July 2017

Abstract

The relationship between genetic variation in CYP2D6 and variable drug response represents a potentially powerful pharmacogenetic tool. However, little is known regarding this relationship in the genetically diverse South African population. The aim was therefore to evaluate the relationship between predicted and measured CYP2D6 phenotype. An XL-PCR+Sequencing approach was used to determine CYP2D6 genotype in 100 healthy volunteers and phenotype was predicted using activity scores. With dextromethorphan as the probe drug, metabolic ratios served as a surrogate measure of in vivo CYP2D6 activity. Three-hour plasma metabolic ratios of dextrorphan/dextromethorphan were measured simultaneously using semi-automated online solid phase extraction coupled with tandem mass spectrometry. Partial adaptation of the activity score system demonstrated a strong association between genotype and phenotype, as illustrated by a kappa value of 0.792, inter-rater discrepancy of 0.051 and sensitivity of 72.7%. Predicted phenotype frequencies using the modified activity score were 1.3% for poor metabolisers (PM), 7.6% for intermediate metabolisers (IM) and 87.3% for extensive metabolisers (EM). Measured phenotype frequencies were 1.3% for PM, 13.9% for IM and 84.8% for EM. Comprehensive CYP2D6 genotyping reliably predicts CYP2D6 activity in this South African cohort and can be utilised as a valuable pharmacogenetic tool.

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Acknowledgements

We would like to thank the South African volunteers who kindly participated in this study as well as Mr Murray Logan and Dr Chrisna Durandt for assisting in sampling. Funding was provided by the Departments of Pharmacology and Immunology and the Institute for Cellular and Molecular Medicine, University of Pretoria; the National Research Foundation of South Africa grant numbers FA2006032700005 and TK2006051500005; the National Health Laboratory Services of South Africa (NHLS); the South African Medical Research Council Unit for Inflammation and Immunity; and Ampath Laboratories, South Africa.

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Correspondence to M S Pepper.

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Dodgen, T., Labuschagne, C., van Schalkwyk, A. et al. Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort. Pharmacogenomics J 16, 566–572 (2016). https://doi.org/10.1038/tpj.2015.76

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