Nat. Med Study: Polygenic Risk Score Model Enables Effective Assessment of Drug-Induced Liver Injury Susceptibility

With the rapid advancement of human genomics research, genome-wide association studies (GWAS) have successfully identified a large number of susceptibility loci for complex diseases, achieving significant success in understanding the genetic factors underlying these conditions. Given that most complex diseases are closely associated with genetic factors, an important strategy is to predict disease risk in populations by incorporating genetic markers alongside environmental risk factors, thereby enabling personalized precision prevention. Emerging from the achievements of genome-wide association studies,Polygenic Risk Score (PRS)Predicting disease risk by integrating information from multiple susceptibility loci has shown initial application value in population risk prediction, optimization of screening strategies, and implementation of precision prevention.

Recently, a joint team from Yokohama City University, the T-CiRA Joint Program, Takeda Pharmaceutical Company Limited, and multiple research institutions in Europe and the United States*Nature Medicine* (Nature Medicine）The journal published an article titled “Polygenic architecture informs potential vulnerability to drug-induced liver injury,”Reports on the latest research findings utilizing polygenic risk scores to predict the risk of drug-induced liver injury (DILI).

Figure: Relevant research was published on September 7 inNature MedicineJournal

Drug-induced liver injury is a leading cause of drug development project termination and market withdrawal, partly due to the inability to identify high-risk patients.This study, by aggregating data from previous large-scale genome-wide association studiesChinaThe effects of the numerous identified genome-wide loci were used to establish a polygenic risk score system for DILI, which was then applied to predict susceptibility to DILI in patients treated with fasiglifam (TAK-875), amoxicillin-clavulanate, or flucloxacillin, as well as in primary hepatocytes and stem cell-derived organoids from multiple donors treated with more than 10 different drugs.Researchers stated that this genetic, cellular, organoid, and human-scale evidence revealsThe Potential Polygenic Architecture of DILI Susceptibility at the Hepatocellular Level, thereby facilitating future mechanistic studies. Furthermore, the study proposed“Polygenicity-in-a-Dish”StrategyIt provides potential information for designing safer, more effective, and more robust clinical trials, marking a significant step forward in addressing longstanding challenges faced by drug developers.

“To date, we have no reliable method to predict whether a drug that is generally effective in the majority of the population will cause liver injury in a small subset of individuals.”Jorge Bezerra, Director of the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children's Hospital Medical Center in the United Statesstated, “This has led to the failure of many promising drugs in clinical trials, and in rare cases, approved medications may also cause serious harm. If we can predict which individuals are at higher risk, we can prescribe medications more confidently.”

Corresponding author of the paper, Dr. Takanori Takebe of Yokohama City UniversityHe has been dedicated to researching methods for the culture and large-scale application of liver organoids, stating, “Our polygenic risk score will become an application similar to consumer-grade diagnostics., such as 23andMe, can directly benefit individuals. People can undergo genetic testing to understand their risk of developing drug-induced liver injury (DILI).”

Figure: Confocal microscopy images of liver organoids in the study

Specifically, this polygenic risk score incorporates more than 20,000 genetic variants. The research team validated the predictive power of the polygenic risk score in cell cultures, organoid tissues, and archived patient genomic data. Furthermore, the polygenic risk score was proven effective in assays involving more than ten drugs, specifically including cyclosporine, bosentan, troglitazone, diclofenac, flutamide, ketoconazole, carbamazepine, amoxicillin–clavulanate, tienilic acid, tacrine, acetaminophen, and tolcapone. Of particular note,The entire testing protocol is applicable to different types of drugs, as the polygenic risk score focuses on a range of common mechanisms involved in hepatic drug metabolism, including oxidative stress pathways and endoplasmic reticulum stress in hepatocytes.

For clinicians, this approach enables rapid genetic testing to identify patients at high risk of liver injury before prescribing medication. Test results may prompt physicians to adjust dosages, schedule more frequent follow-up examinations to detect early signs of liver injury, or switch medications entirely. In drug development, this testing strategy can exclude individuals at high risk of liver injury from clinical trials, thereby allowing for a more accurate assessment of the drug’s benefits.The researchers ultimately emphasized that further large-scale population studies are needed to confirm the preliminary findings and expand DILI screening.

References:

1. Koido, M., Kawakami, E., Fukumura, J. et al. Polygenic architecture informs potential vulnerability to drug-induced liver injury. Nat Med (2020). https://doi.org/10.1038/s41591-020-1023-0

2. Gene Test Can Predict Risk of Medications Causing Liver Injury

https://scienceblog.cincinnatichildrens.org/gene-test-can-predict-risk-of-medications-causing-liver-injury/?_ga=2.219194073.1987748286.1599712974-1072995071.1599712974

3. Chinese Journal of Epidemiology. Polygenic Risk Scores for Risk Prediction and Precision Prevention of Complex Diseases: Opportunities and Challenges

DOI：10.3760/cma.j.issn.0254-6450.2019.09.001