A pathway-driven predictive model of tramadol pharmacogenetics

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http://hdl.handle.net/10138/316324

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Wendt , F R , Novroski , N M M , Rahikainen , A-L , Sajantila , A & Budowle , B 2019 , ' A pathway-driven predictive model of tramadol pharmacogenetics ' , European Journal of Human Genetics , vol. 27 , no. 7 , pp. 1143-1156 . https://doi.org/10.1038/s41431-019-0369-6

Title: A pathway-driven predictive model of tramadol pharmacogenetics
Author: Wendt, Frank R.; Novroski, Nicole M. M.; Rahikainen, Anna-Liina; Sajantila, Antti; Budowle, Bruce
Contributor: University of Helsinki, Department of Forensic Medicine
University of Helsinki, Department of Forensic Medicine
Date: 2019-07
Language: eng
Number of pages: 14
Belongs to series: European Journal of Human Genetics
ISSN: 1018-4813
URI: http://hdl.handle.net/10138/316324
Abstract: Predicting metabolizer phenotype (MP) is typically performed using data from a single gene. Cytochrome p450 family 2 subfamily D polypeptide 6 (CYP2D6) is considered the primary gene for predicting MP in reference to approximately 30% of marketed drugs and endogenous toxins. CYP2D6 predictions have proven clinically effective but also have well-documented inaccuracies due to relatively high genotype-phenotype discordance in certain populations. Herein, a pathway-driven predictive model employs genetic data from uridine diphosphate glucuronosyltransferase, family 1, polypeptide B7 (UGT2B7), adenosine triphosphate (ATP)-binding cassette, subfamily B, number 1 (ABCB1), opioid receptor mu 1 (OPRM1), and catechol-O-methyltransferase (COMT) to predict the tramadol to primary metabolite ratio (T:M1) and the resulting toxicologically inferred MP (t-MP). These data were then combined with CYP2D6 data to evaluate performance of a fully combinatorial model relative to CYP2D6 alone. These data identify UGT2B7 as a potentially significant explanatory marker for T:M1 variability in a population of tramadol-exposed individuals of Finnish ancestry. Supervised machine learning and feature selection were used to demonstrate that a set of 16 loci from 5 genes can predict t-MP with over 90% accuracy, depending on t-MP category and algorithm, which was significantly greater than predictions made by CYP2D6 alone.
Subject: METABOLITE RATIOS
P-GLYCOPROTEIN
CYP2D6
GENOTYPE
PHENOTYPE
DISCORDANCE
FRAMEWORK
POLYMORPHISMS
CONSEQUENCES
ASSOCIATION
1182 Biochemistry, cell and molecular biology
1184 Genetics, developmental biology, physiology
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