A common genetic variant in the ETS1 gene increases the risk of developing primary biliary cholangitis (PBC), according to research on Han Chinese populations published recently in Clinical Reviews in Allergy and Immunology.
The variant, known as rs10893900, alters gene activity in immune cells and helps explain why certain people are more likely to develop the disease. The results could lead to better risk prediction and future treatment strategies aimed at regulating immune responses.
“[O]ur study confirmed that rs10893900 is associated with genetic risk for PBC in Han Chinese populations,” explained this study’s authors. “Our in silico analysis provides the insights that ETS1 is involved in JAK-STAT signaling pathway, further influencing the T initiated autoimmune response.”
Researchers analyzed genetic data from 3,184 cases of PBC and 7,324 healthy controls and confirmed that rs10893900 is a significant risk factor for PBC. Located between two genes, ETS1 and FLI1, the variant was found to have stronger regulatory effects on ETS1. Laboratory tests showed that the “G” version of the variant increased ETS1 gene activity by more than fourfold compared to the “A” version.
Read more about causes and risk factors for PBC
ETS1 and FLI1 both play important roles in immune regulation, but this study found that ETS1 was more closely linked to PBC. The variant influences how transcription factors, which are proteins that control gene expression, bind to DNA. The stronger binding caused by the G allele enhanced ETS1 activity in immune cells, including natural killer, B and various T cell types. This excessive activation may promote inflammation and damage in liver tissue.
Patients with severe PBC, especially those who do not respond to standard therapy with ursodeoxycholic acid, showed higher ETS1 expression in liver tissue compared to those with milder disease or healthy individuals. Animal models of autoimmune liver disease also exhibited increased ETS1 and FLI1 activity, reinforcing the gene’s link to immune-related liver injury.
Additional analyses revealed that ETS1 interacts with the JAK-STAT signaling pathway, a key driver of immune activity and inflammation. Individuals carrying risk genotypes at both ETS1 and JAK1 had nearly three times greater odds of developing PBC.
For patients, these findings emphasize the growing importance of genetics in understanding autoimmune diseases. Identifying risk variants like rs10893900 could enable earlier detection, more personalized treatment, and eventually, targeted therapies that help rebalance the immune system and prevent liver damage.
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