7 genes identified as potential biliary atresia treatment targets
Study suggests immune cells may play a role
Researchers identified seven genes that may contribute to biliary atresia, a discovery that could provide opportunities to develop treatments or biological markers for the disease.
Many of the identified genes play a role in the immune system. The researchers said this suggests that therapies targeting related immune processes might be able to address disease-causing mechanisms. Analyzing the activity of such genes in babies with biliary atresia could also support future precision medicine approaches to choosing appropriate, individualized therapies.
“This study not only reinforces the current body of knowledge but also lays the groundwork for developing precise immunotherapy strategies for BA [biliary atresia], offering new directions for future exploration,” the research team wrote.
The study, “Immune and genetic landscapes of biliary atresia: a pathway to precision medicine,” was published in BMC Pediatrics.
Biliary atresia is a rare infant liver disease in which the tubes that carry bile from the liver to the small intestine are blocked or absent. When bile, a digestive fluid, backs up in the liver, it can damage the organ. Bile accumulation may also lead to biliary atresia symptoms, including jaundice, a yellowing of the skin and eyes. These symptoms usually appear within the first few weeks after birth.
Kasai surgery does not guarantee cure
A surgical procedure called Kasai portoenterostomy is the primary first-line treatment for biliary atresia. If performed early enough, it can restore the normal flow of bile, easing symptoms and preventing further damage.
However, children undergoing the procedure may still develop liver problems, including inflammation and scarring (fibrosis), later in life. If the liver fails, a liver transplant may be the only therapeutic option.
“The high cost associated with transplantation and the lifelong use of immunosuppressive therapy impose significant financial and psychological burdens on patients and their families,” the researchers wrote.
Treatments that influence biliary atresia processes could help sustain liver function recovery. However, developing such therapies is challenging because scientists don’t entirely understand the underlying causes of biliary atresia.
The team aimed to find genes with a potential role in biliary atresia development. These genes could guide approaches to future experimental therapies.
The team began by analyzing two biliary atresia-related datasets with information about gene activity levels. They involved 111 people with biliary atresia and seven healthy people.
They found 816 genes whose activity levels were significantly different between the biliary atresia and control groups: 458 with higher activity and 358 with lower activity. This suggested an association between gene activity and disease state, but not necessarily a causal relationship in which gene activity differences led to biliary atresia.
By combining these findings with results from a different statistical method that analyzes genetic variations and their frequency in people with and without biliary atresia, the researchers were able to identify seven likely causal genes.
Four of these (C12orf75, PSD3, CRIM1, CHIT1) had significantly higher activity in biliary atresia participants, while three (SEC14L4, MAPRE3, TCEA3) were significantly less active.
Further analyses showed significant associations between these genes’ activity and the amount of certain types and subtypes of immune cells, suggesting their involvement in immune responses that may contribute to biliary atresia.
“These genes provide new insights into the genetic basis of [biliary atresia], revealing potential molecular changes that drive disease progression,” the team wrote.
Liver sample comparison bolsters results
Next, the researchers compared the activity of these genes in liver samples from 20 infants with biliary atresia and 10 healthy controls. Four out of the seven identified genes followed the previously observed patterns in these samples, “supporting the robustness of our results,” the team wrote.
Specifically, C12orf75, PSD3, and CHIT1 showed higher activity in biliary atresia samples. These genes, which have been linked with several cellular processes and autoimmune diseases, could provide insight into the biliary atresia microenvironment, or the local cells and molecules that contribute to the disease.
CHIT1, the protein coded by the CHIT1 gene, marks activation of a type of immune cell called macrophages and “is involved in tissue repair and inflammatory responses,” the researchers wrote.
“The upregulation of CHIT1 indicates the importance of macrophages in the immune microenvironment of [biliary atresia], potentially promoting chronic inflammation and fibrosis of the bile ducts,” they wrote.
The TCEA3 gene, which regulates the activity of other genes, was also significantly less active in samples from infants with biliary atresia.
Identifying these four genes, as well as the three others implicated in the initial analysis, could be a first step to developing disease-modifying therapies. Further investigations could solidify the causal link between the identified genes and biliary atresia and evaluate whether these genes are potential therapeutic targets, according to the researchers.
