Significant association between <i>HLA‐B*35:01</i> and onset of drug‐induced liver injury caused by Kampo medicines in Japanese patients
Ryosuke Nakamura, Noriaki Arakawa, Yoïchi Tanaka, Nahoko Uchiyama, Akihiro Sekine, Yoichi Mashimo, Keiji Tsuji, Tatehiro Kagawa, Ken Sato, Masaaki Watanabe, Mitsuhiko Aiso, Yoichi Hiasa, Yoshiyuki Takei, Hiromasa Ohira, Minoru Ayada, Eri Tsukagoshi, Keiko Maekawa, Masahiro Tohkin, Yoshiro Saito, Hajime Takikawa
Abstract
Abstract Aim Drug‐induced liver injury (DILI) is a severe and life‐threatening immune‐mediated adverse effect, occurring rarely among treated patients. We examined genomic biomarkers in the Japanese population that predict the onset of DILI after using a certain class of drugs, such as Kampo products (Japanese traditional medicines). Methods A total of 287 patients diagnosed as DILI by hepatology specialists were recruited after written informed consent was obtained. A genome‐wide association analysis and human leukocyte antigen (HLA) typing in four digits were performed. Results We found a significant association ( p = 9.41 × 10 −10 ) of rs146644517 ( G > A ) with Kampo product–related DILI. As this polymorphism is located in the HLA region, we evaluated the association of HLA types and found that 12 (63.2%) of 19 Kampo‐DILI patients contained HLA‐B*35:01 , whereas only 15.2% were positive for this HLA among healthy volunteers. The odds ratio was 9.56 (95% confidence interval 3.75–24.46; p = 2.98 × 10 −6 , corrected p = 4.17 × 10 −5 ), and it increased to 13.55 compared with the DILI patients not exposed to Kampo products. The individual crude drug components in the Kampo products, including Scutellaria root ( ougon in Japanese), rhubarb ( daiou ), Gardenia fruit ( sanshishi ), and Glycyrrhiza ( kanzou ), were significantly associated with HLA‐B*35:01 . Conclusions HLA‐B*35:01 is a genetic risk factor and a potential predictive biomarker for Kampo‐induced DILI in the Japanese population.