CHST3 and CHST13 polymorphisms as predictors of bosentan-induced liver toxicity in Japanese patients with pulmonary arterial hypertension. (September 2018)

• Record Type: Journal Article
• Authors: Yorifuji, Kennosuke; Uemura, Yuko; Horibata, Shinji; Tsuji, Goh; Suzuki, Yoko; Miyagawa, Kazuya; Nakayama, Kazuhiko; Hirata, Ken-ichi; Kumagai, Shunichi; Emoto, Noriaki
• Is Part Of: Pharmacological research. Volume 135(2018)
• Page Start: 259
• Page End: 264
• Publication Date: 2018-09
• Subjects: Bosentan -- Pulmonary arterial hypertension -- Proteoglycan -- DMET -- Asian -- Drug metabolism enzymes and transporters -- Affimetrix -- Pharmacogenomics -- Pharmacogenetics; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2018.08.011
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Bosentan, an endothelin receptor antagonist, has been widely used as a first-line drug for the treatment of pulmonary arterial hypertension (PAH). In addition, bosentan is approved for patients with digital ulcers related to systemic sclerosis. Liver dysfunction is a major adverse effect of bosentan and may lead to discontinuation of therapy. The purpose of this study was to identify genomic biomarkers to predict bosentan-induced liver injury. A total of 69 PAH patients were recruited into the study. An exploratory analysis of 1936 single-nucleotide polymorphisms (SNPs) in 231 genes involved in absorption, distribution, metabolism, and elimination of multiple medications using Affimetrix DMET™ (Drug Metabolism Enzymes and Transporters) chips was performed. We extracted 16 SNPs ( P < 0.05) using the Jonckheere-Terpstra trend test and multiplex logistic analysis; we identified two SNPs in two genes, CHST3 and CHST13, which are responsible for proteoglycan sulfation and were significantly associated with bosentan-induced liver injury. We constructed a predictive model for bosentan-induced liver injury (area under the curve [AUC]: 0.89, sensitivity: 82.61%, specificity: 86.05%) via receiver operating curve (ROC) analysis using 2 SNPs and 2 non-genetic factors. Two SNPs were identified as potential predictive markers for bosentan-induced liver injury in Japanese patients with pulmonary arterial hypertension. This is the first pharmacogenomics study linking proteoglycan sulfating genes to drug-induced liver dysfunction, a frequently observed clinical adverse effect of bosentan therapy. These results may provide a way to personalize PAH medicine as well as provide novel mechanistic insights to drug-induced liver dysfunction.