Significant association between HLA‐B*35:01 and onset of drug‐induced liver injury caused by Kampo medicines in Japanese patients

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.

Overview of diagnostic laboratory tests and diagnostic criteria for liver injury caused by Kampo medicine

“…The diagnosis of KMILI remains challenging, and we sincerely await the development of reliable biomarkers for KMILI. Several studies are underway on the usefulness of HLA in the diagnosis of KMILI [16,17].…”

The clinical application of genetic testing in DILI, are we there yet?

“…Polygonum multiflorum HLA-B*35:01 Chinese [13,36,37] Green tea extract HLA-B*35:01 Multiple ethnicities [10,13] Garcinia cambogia + green tea HLA-B*35:01 European American [10,38] Hydroxycut + green tea HLA-B*35:01 - [39] Turmeric + curcumin HLA-B*35:01 European American [40] Kampo medicines HLA-B*35:01 HLA-C*03:03 Japanese [36,41] Note: This table represents a comprehensive summary of various drugs associated with DILI and their commonly linked alleles. The sensitivity and specificity are listed for some of these alleles, along with the PPV and NPV per the general population.…”

Yin/Yang associated differential responses to Psoralea corylifolia Linn. In rat models: an integrated metabolomics and transcriptomics study

“…As reported in recent years, liver damages induced by Polygonum multiflorum Thunb., Green Tea, and Kampo products (Japanese traditional medicines), etc. are closely related to HLA-B*35:01 [ 10 – 12 ], while liver damage induced by flucloxacillin, pazopanib, abacavir, etc. are closely related to HLA-B*57:01 [ 13 – 17 ].…”