Association between HLA-B*35:01 and onset of drug-induced liver injury caused by Kampo medicines in Japanese

Abstract

[Backgrounds] Drug-induced liver injury (DILI) is a severe and life-threatening immune-mediated adverse reaction, occurring rarely among treated patients. We explored 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 subjects 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 adjacent to the HLA region, we evaluated the association of HLA types and found that 12 (63.2%) of 19 Kampo-DILI cases had 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 cases 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.