Genetic factors associated with gemcitabine pharmacokinetics, disposition, and toxicity

Jonathan Knights, Yasunori Sato, Nahoko Kaniwa, Yoshiro Saito, Hideki Ueno, Murali Ramanathan

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

AIM: The goal of this work was to investigate the associations of genetic and environmental factors with gemcitabine disposition and toxicity from genomewide data using a novel information theoretic approach. METHODS: We utilized the information theoretic K-way interaction information (KWII) metric to detect gene-gene and gene-environment interactions associated with gemcitabine disposition and gemcitabine-induced neutropenia in genomic and clinical data from Japanese cancer patients. RESULTS: The information theoretic KWII analyses identified age and four genes - DMD, HEXDC, CNTN4, and ALOX5AP - to be associated with gemcitabine pharmacokinetics (PK). The rs4769060 single-nucleotide polymorphism in the ALOX5AP gene was associated with all PK parameters studied. For gemcitabine-induced neutropenia, multiple associations with long intergenic noncoding RNA regions were detected. Pathway analysis identified leukotriene and eoxin synthesis, platelet homeostasis, and L1CAM interactions as potential pathways associated with gemcitabine disposition. CONCLUSION: The KWII analyses detected novel associations with gemcitabine PK and toxicity. These results could be used to inform future investigations involving gemcitabine efficacy in clinical settings.

Original languageEnglish
Pages (from-to)15-25
Number of pages11
JournalPharmacogenetics and Genomics
Volume24
Issue number1
DOIs
Publication statusPublished - 2014 Jan 1
Externally publishedYes

Keywords

  • Gemcitabine
  • Gene-environment interactions
  • Gene-gene interactions
  • K-way interaction information
  • Pharmacometrics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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