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A genome-wide association study of tramadol metabolism from post-mortem samples

The Pharmacogenomics Journal volume 20, pages 94–103 (2020)Cite this article

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Abstract

Phase I tramadol metabolism requires cytochrome p450 family 2, subfamily D, polypeptide 6 (CYP2D6) to form O-desmethyltramadol (M1). CYP2D6 genetic variants may infer metabolizer phenotype; however, drug ADME (absorption, distribution, metabolism, and excretion) and response depend on protein pathway(s), not CYP2D6 alone. There is a paucity of data regarding the contribution of trans-acting proteins to idiosyncratic phenotypes following drug exposure. A genome-wide association study identified five markers (rs79983226/kgp11274252, rs9384825, rs62435418/kgp10370907, rs72732317/kgp3743668, and rs184199168/exm1592932) associated with the conversion of tramadol to M1 (M1:T). These SNPs reside within five genes previously implicated with adverse reactions. Analysis of accompanying toxicological meta-data revealed a significant positive linear relationship between M1:T and degree of sample polypharmacy. Taken together, these data identify candidate loci for potential clinical inferences of phenotype following exposure to tramadol and highlight sample polypharmacy as a possible diagnostic covariate in post-mortem genetic studies.

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Acknowledgements

The authors thank Jie Sun, Talisa Silzer, and Dr. Nicole Phillips and Dr. August Woerner from the University of North Texas Health Science Center Department of Microbiology, Immunology, and Genetics and Center for Human Identification for their suggestions with sample preparation, imaging, and data processing. We also thank Al Bodota from Illumina for his reagent and product management support. The data presented were ancillary data generated with support of a previous project from the Department of Defense (DoD) to Parabon Computation, Inc. and Parabon NanoLabs, Inc. and sub-contracted to UNTHSC (No. 20160926-UNTHSC-SUB0085-01). The opinions and findings presented here are those of the authors and do not necessarily reflect those of the DoD, Parabon Computation, Inc., or Parabon NanoLabs, Inc.

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  1. Center for Human Identification, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA

    Frank R. Wendt, Jonathan L. King & Bruce Budowle

  2. Department of Forensic Medicine, University of Helsinki, P.O Box 40, 00014, Helsinki, Finland

    Anna-Liina Rahikainen & Antti Sajantila

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Wendt, F.R., Rahikainen, AL., King, J.L. et al. A genome-wide association study of tramadol metabolism from post-mortem samples. Pharmacogenomics J 20, 94–103 (2020). https://doi.org/10.1038/s41397-019-0088-y

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