Genetic factors associated with gemcitabine pharmacokinetics, disposition, and toxicity.
OBJECTIVE
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.


CONCLUSIONS
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.
aDepartment of Pharmaceutical Sciences, State University of New York, Buffalo, New York, USA bClinical Research Center, Chiba University School of Medicine, Chiba cDivision of Medicinal Safety Science, National Institute of Health Sciences dHepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
Jonathan
J
Knights
Yasunori
Y
Sato
Nahoko
N
Kaniwa
Yoshiro
Y
Saito
Hideki
H
Ueno
Murali
M
Ramanathan
D058927:5-Lipoxygenase-Activating Proteins / Q000235:genetics*; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics*; D044466:Asian People / Q000235:genetics; D002986:Clinical Trials as Topic; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D059647:Gene-Environment Interaction; D005819:Genetic Markers; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D009503:Neutropenia / Q000139:chemically induced; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics; D000093542:Gemcitabine
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D000964:Antimetabolites, Antineoplastic; D005819:Genetic Markers; D003841:Deoxycytidine; D000093542:Gemcitabine