A pathway-driven predictive model of tramadol pharmacogenetics

Frank R. Wendt, Nicole M.M. Novroski, Anna Liina Rahikainen, Antti Sajantila, Bruce Budowle

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1143-1156
Number of pages14
JournalEuropean Journal of Human Genetics
Volume27
Issue number7
DOIs
StatePublished - 1 Jul 2019

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Tramadol
Pharmacogenetics
Peptides
Phenotype
Genes
Catechol O-Methyltransferase
Glucuronosyltransferase
Uridine Diphosphate
mu Opioid Receptor
Genetic Models
Population
Adenosine Triphosphate
Cytochrome P450 Family 2
Pharmaceutical Preparations

Cite this

Wendt, Frank R. ; Novroski, Nicole M.M. ; Rahikainen, Anna Liina ; Sajantila, Antti ; Budowle, Bruce. / A pathway-driven predictive model of tramadol pharmacogenetics. In: European Journal of Human Genetics. 2019 ; Vol. 27, No. 7. pp. 1143-1156.
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A pathway-driven predictive model of tramadol pharmacogenetics. / Wendt, Frank R.; Novroski, Nicole M.M.; Rahikainen, Anna Liina; Sajantila, Antti; Budowle, Bruce.

In: European Journal of Human Genetics, Vol. 27, No. 7, 01.07.2019, p. 1143-1156.

Research output: Contribution to journalArticle

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