NEW YORK – A team from Japan, the US, and the UK has developed a series of polygenic risk scores (PRS) for drug-induced liver injury (DILI) using available genetic data in combination with findings from cell culture and organoid experiments.
Along with work done to find the PRS, the investigators "used the derived PRS to identify mechanisms underlying the susceptibility to DILI," senior author Takanori Takebe, a researcher affiliated with Cincinnati Children's Hospital, the Cincinnati College of Medicine, Yokohama City University, and other centers in Japan, , and his colleagues wrote.
The authors explained that drug-related liver injury contributes to morbidity and mortality. It is also responsible for stalled drug development programs and side effects that prompt individuals to stop taking available treatments.
For a paper published in Nature Medicine on Monday, Takebe and colleagues brought together summary statistics and risk locus data from prior genome-wide association studies performed by members of the international drug-induced livery injury consortium and drug-induced liver injury network, which looked across forms of DILI (ALL-DILI), or focused on hepatocellular injury forms of DILI (HC-DILI) and forms of DILI that involve cholestatic injury (CM-DILI), which is characterized by higher-than-usual levels of bilirubin and other liver injury markers.
"These findings can also provide fundamental mechanisms defining CM-DILI and might ultimately contribute to the design of safer, efficient, and more robust clinical trials," the authors reported. "More broadly, the proposed 'polygenicity-in-a-dish' strategy is a powerful approach to investigate and interrogate highly complicated pathogenesis in humans with minimal confounding factors."
Using GWAS data for 862 ALL-DILI patients, 474 individuals with HC-DILI, and 3,223 individuals with CM-DILI, along with almost 10,600 unaffected controls, the team tracked down PRS that appeared to coincide with liver injury after exposure to a G-protein-coupled receptor agonist drug candidate from Takeda called fasiglifam or TAK-875, to a combination of antibiotics amoxicillin and clavulanate, or to the beta-lactam antibiotic flucloxacillin.
In a set of follow-up functional enrichment analyses, the risk scores also provided clues to liver injury risk in primary hepatocyte cell cultures or in liver cell organoids developed from stem cells using a broader set of drug exposures. By incorporating network, in silico screening, cell line SNP data, transcriptome profiles, and pathway information, the investigators tracked down a PRS that showed promise for picking up individuals prone to CM-DILI, as well as those who are at risk of other forms of DILI in response to a range of other drugs.
"Our [genome-wide PRS] for CM-DILI revealed shared DILI predictivity across a variety of drugs independent of their individual chemical characteristics that are considered important," the authors wrote. "This indicates that the makeup of our polygenic scores relates to intra-hepatocyte mechanisms leading to hepatotoxicity."