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Genetic variant linked to drug-induced liver injury

In the largest, international drug-induced liver injury (DILI) genetic study to date, researchers found that a genetic variant implicated in autoimmune diseases increases the risk of liver injury triggered by a range of drugs. DILI is one of the most common causes of acute liver failure in the United States. It is also one of the most frequent obstacles in the development and approval of new drugs. Yet it is difficult to prevent DILI because of its rarity, the lack of specific diagnostics, and the unidentified disease-causing characteristics unique to each individual. Scientists have been studying people who experienced DILI to determine if genetics play a role. Thus far, several human leukocyte antigen (HLA) genes, which are responsible for regulating the immune system, have been associated with DILI, which means that at least some cases of DILI may result from an improper immune response to the drug or its metabolites (breakdown products). Other genes have been implicated in DILI, but studies have been too small to conclusively link them to liver injury.

In this study, researchers in NIDDK’s Drug-Induced Liver Injury Network (DILIN), in collaboration with an international consortium, analyzed the genomes of over 2,000 men and women who had experienced DILI and compared them to the genomes of over 12,000 people who have not. Analyzing the genomes of this diverse cohort, including individuals of European, African-American, and Hispanic descent, they found a variant of a gene called PTPN22 that is more common in people who had experienced DILI triggered by a range of drugs. This is the first DILI genetic variant discovered that is linked to such a range of drugs, as opposed to one specific drug, although it is most strongly linked to liver injury caused by an antibiotic called amoxicillin-clavulanate—the most common cause of DILI after acetaminophen in the United States. In fact, among people who have the HLA variants that are linked to liver injury caused by amoxicillin-clavulanate, this PTPN22 variant almost doubles the risk of DILI.

This variant of PTPN22 is the first outside of the HLA genes that was found to be conclusively linked to DILI. The identification of this variant could help prevent cases of DILI. For example, knowing that a person is genetically susceptible to liver injury caused by amoxicillin-clavulanate could help health care providers come up with a more ideal drug regimen for that individual—a form of precision medicine. Also, this genetic variant has been previously linked to several autoimmune diseases, such as type 1 diabetes, arthritis, and lupus, so this study offers further evidence that DILI may result from an improper immune reaction triggered by exposure to a drug or its metabolites. This knowledge could help to develop new treatments for DILI that are designed to curb the immune response.

Cirulli ET, Nicoletti P, Abramson K,…Watkins PB; Drug-Induced Liver Injury Network (DILIN) Investigators and International DILI Consortium (iDILIC). A missense variant in PTPN22 is a risk factor for drug-induced liver injury. Gastroenterology. 156: 1707-1716, 2019.

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