Gene-Specific Variant Classifier (DPYD-Varifier) to Identify Deleterious Alleles of Dihydropyrimidine Dehydrogenase

Clin Pharmacol Ther. 2018 Oct;104(4):709-718. doi: 10.1002/cpt.1020. Epub 2018 Feb 2.


Deleterious variants in dihydropyrimidine dehydrogenase (DPD, DPYD gene) can be highly predictive of clinical toxicity to the widely prescribed chemotherapeutic 5-fluorouracil (5-FU). However, there are very limited data pertaining to the functional consequences of the >450 reported no-synonymous DPYD variants. We developed a DPYD-specific variant classifier (DPYD-Varifier) using machine learning and in vitro functional data for 156 missense DPYD variants. The developed model showed 85% accuracy and outperformed other in silico prediction tools. An examination of feature importance within the model provided additional insight into functional aspects of the DPD protein relevant to 5-FU toxicity. In the absence of clinical data for unstudied variants, prediction tools like DPYD-Varifier have great potential to individualize medicine and improve the clinical decision-making process.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antimetabolites, Antineoplastic / metabolism
  • Antimetabolites, Antineoplastic / toxicity*
  • Cell Survival / drug effects
  • Computer Simulation*
  • Dihydrouracil Dehydrogenase (NADP) / chemistry
  • Dihydrouracil Dehydrogenase (NADP) / genetics*
  • Dihydrouracil Dehydrogenase (NADP) / metabolism
  • Dose-Response Relationship, Drug
  • Fluorouracil / metabolism
  • Fluorouracil / toxicity*
  • Gene Frequency
  • Genotype
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Inhibitory Concentration 50
  • Machine Learning*
  • Models, Molecular
  • Mutation, Missense*
  • Pharmacogenetics / methods*
  • Pharmacogenomic Testing / methods*
  • Pharmacogenomic Variants*
  • Predictive Value of Tests
  • Protein Conformation
  • Risk Assessment
  • Structure-Activity Relationship


  • Antimetabolites, Antineoplastic
  • Dihydrouracil Dehydrogenase (NADP)
  • Fluorouracil