A Polygenic Risk Score Helps Predict Adverse Liver Effects of Medications

Cincinnati, OH—In the near future, a “polygenic risk score” might be available to indicate when an approved or experimental medication is likely to cause drug-induced liver injury (DILI).

That’s according to an article in Nature Medicine which describes work conducted by a consortium of scientists from Cincinnati Children’s Hospital, Tokyo Medical and Dental University, Takeda Pharmaceutical Co. in Japan, and several other research centers in Japan, Europe and the United States.

“So far we have had no reliable way of determining in advance whether a medication that usually works well in most people might cause liver injury among a few,” said Jorge Bezerra, MD, Director, Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children’s.

“That has caused a number of promising medications to fail during clinical trials, and in rare cases, also can cause serious injury from approved medications. If we could predict which individuals would be most at-risk, we could prescribe more medications with more confidence,” explained Dr. Bezerra, who was not involved with the study.

Now that reliable test might be just around the corner.

In this case, the polygenic risk score predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillin–clavulanate, or flucloxacillin and in primary hepatocytes and stem cell-derived organoids from multiple donors treated with more than 10 different drugs.  

“Our genetic score will potentially benefit people directly as a consumer diagnostic-like application, such as 23andMe and others. People could take the genetic test and know their risk of developing DILI,” pointed out corresponding author Takanori Takebe, MD, an organoid expert at Cincinnati Children’s.

The risk score was developed by re-analyzing hundreds of genome-wide association studies (GWAS) that had identified a long list of gene variants that might indicate a likelihood of a poor reaction in the liver to various compounds. 

The resulting risk score takes more than 20,000 gene variants into account, and its prediction power was confirmed in cell culture, in organoid tissue and by using patient genomic data already on file. The score was shown to be valid in tests involving more than a dozen medications, including cyclosporine, bosentan, troglitazone, diclofenac, flutamide, ketoconazole, carbamazepine, amoxicillin-clavulanate, methapyrilene. tacrine, acetaminophen, and tolcapone.

The score takes into account common mechanisms involved in how the liver metabolizes a drug, including oxidant stress pathways in liver cells and endoplasmic reticulum (ER) stress--a disruption of cell function that happens when proteins cannot fold properly.

The authors suggest that, in the future, clinicians would be able to run a rapid genetic test to identify patients at higher risk of liver injury before prescribing medications. Then, a decision could be made to change the dosage, order more frequent follow-up tests to catch early signs of liver damage, or switch to a different medication.
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