Identification of the genomic biomarkers of bosentan-induced liver dysfunction

[Speaker] Kennosuke Yorifuji:1,2,3
[Co-author] Yuko Uemura:2, Shinji Horibata:2,3, Goh Tsuji:2,4, Yoko Suzuki:1,5, Kazuya Miyagawa:1,5, Kazuhiko Nakayama:5, Ken-Ichi Hirata:5, Shunichi Kumagai:2,4, Noriaki Emoto:1,5
1:Clinical Pharmacy, Kobe Pharmaceutical University, Japan, 2:The Shinko Institute for Medical Research, Japan, 3:Department of Pharmacy, shinko hospital, Japan, 4:Center for Rheumatic Diseases, shinko hospital, Japan, 5:Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe Graduate School of Medicine, Japan

[Background] Pulmonary arterial hypertension (PAH) is a progressive and devastating disease, ultimately leading to death from right heart failure if left untreated. Bosentan, an endothelin receptor antagonist, is used as a first-line drug for the treatment of PAH. Also, bosentan is the only drug having an insurance application for the onset suppression of the finger ulcer in systemic scleroderma. It's major adverse effect is a liver dysfunction, approximately 10% of patients treated with bosentan show dose-dependent increases in hepatic aminotransferases, which may lead to discontinuation of therapy. In the past two decades, the remarkable development of various disease-targeted medications, including prostanoids, phosphodiesterase-5 inhibitors, and endothelin receptor antagonists, has dramatically improved the management of patients with PAH. Therefore, we can avoid high risk pharmacotherapy if risk assessment is enabled before administration.
[Objective] The purpose of this study was to identify genomic biomarkers of the bosentan-induced liver injury. And we construct a predictive model which enable realization of the personalized medicine.
[Methods] A total of 69 PH patients at Kobe University Hospital or Shinko Hospital were recruited into the study from March, 2013 to July, 2013. An exploratory analysis of 1,936 single-nucleotide polymorphisms (SNPs) in 231 genes involved in absorption, distribution, metabolism, and elimination of multiple medications using DMET chips was performed.
[Results] We extracted 16 SNPs which became p < 0.05 using Jonckheere-Terpstra trend test, and by using multiplex logistic analysis, we identified two SNPs in two genes, CHST3, and CHST13 significantly associated with bosentan-induced liver injury. We conducted ROC analysis by using 2 SNPs and 2 items of non-genetic factor, and we constructed predictive model for bosentan-induced liver injury. (AUC: 0.89 Sensitivity: 82.61% Specificity: 86.05%) The CHST gene which we extracted this study is involved in sulfation of the chondroitin sulfate, and there is no report about the metabolism of bosentan association with CHST gene.
[Conclusion] Two SNPs were identified as new potential predictive markers for bosentan-induced liver injury. These results may provide not only a way to personalized medicine for PH but also the discussion of a new biologic study on drug-induced liver dysfunction.
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