Gene-variant score helps predict risk of drug-induced liver injury

Last Updated: 2020-09-16

By David Douglas

NEW YORK (Reuters Health) - A polygenic risk score (PRS) that can predict susceptibility to drug-induced liver injury (DILI) could help increase the safety and efficacy of drug trials, according to a international group of researchers.

"DILI is a rare yet highly unpredictable disorder" that often leads to termination of drug development or withdrawal from the market, explained Dr. Takanori Takebe of the University of Cincinnati College of Medicine, in Ohio. This not only disappoints patients, he told Reuters Health by email, but has a significant impact on the financial risk to pharmaceutical companies.

In a paper in Nature Medicine, Dr. Takebe and colleagues note that genome-wide association studies (GWAS) conducted by the Drug-Induced Liver Injury Consortium and the Drug-Induced Liver Injury Network have identified several significant variants associated with DILI due to multiple different drugs.

But each variant has modest predictive effect. By aggregating the effects of genome-wide loci, the researchers developed a PRS that takes more than 20,000 gene variants into account.

The score, they say, "predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillinclavulanate or flucloxacillin and in primary hepatocytes and stem cell-derived organoids from multiple donors treated with over ten different drugs."

Pathway analysis highlighted previously implicated processes, including unfolded protein responses and oxidative stress. Further screening identified compounds that elicit transcriptomic signatures seen in hepatocytes from people with an elevated PRS. This suggests mechanistic links and use as a novel screen for the safety of new drug candidates, the researchers say.

Dr. Takebe concluded, "If a pharmaceutical company adopts in vitro high-risk human organoid testing as part of preclinical development this may increase the success probability of clinical trial by minimizing DILI risk." And, he added, "Polygenic genetic diagnostic testing might inform an individual's risk of DILI caused by medications beforehand."

Dr. Yasuko Iwakiri of Yale University School of Medicine, in New Haven, Connecticut, who specializes in liver disease, told Reuters Health by email that "this is a highly innovative, elegant and exciting study."

"Dr. Takebes group," she added, "has identified genomic profiles that may enable us to predict individuals with the likelihood of the development of drug-induced liver injury, a serious side effect of drugs and supplements. The finding is also helpful for the development of drugs with minimal toxicity. I think this is a great example of precision medicine."

The study was funded in part by Takeda Pharmaceutical Company. Dr. Takebe received support from Takeda and a number of authors are employees of the company.

SOURCE: https://go.nature.com/3kl88J6 Nature Medicine, online September 7, 2020.