, according to a study published in Gastro Hep Advances.
PSC is very rare, with an incidence of 0-1.3 cases per 100,000 people per year. Because up to 80% of patients with PSC also have inflammatory bowel disease (IBD), a link along the gut-liver axis is suspected. So far, scientists have not understood the causes of PSC, the main complications of which include biliary cirrhosis, bacterial cholangitis, and cholangiocarcinoma.
No treatment is currently available for PSC, but the findings of this genomics study suggest several targets that may be worth pursuing, particularly the gene NR0B2.
“The therapeutic targeting of NR0B2 may potentiate that of FXR [farnesoid X receptor] and enable action on early events of the disease and prevent its progression,” wrote Christophe Desterke, PhD, of the Paul-Brousse Hospital, the French National Institute of Health and Medical Research, and the University of Paris-Saclay in Villejuif, France, and his associates.
The researchers used an algorithmic tool to mine the MEDLINE/PubMed/NCBI database using the three key symptoms of PSC – biliary fibrosis, biliary inflammation, and biliary stasis – as their keywords. This approach allowed them to discover the genes and potential pathways related to PSC in published research text or in clinical, animal, and cellular models.
The researchers initially found 525 genes linked to PSC and then compared them to RNA data from liver biopsies taken from patients with liver disease from various causes. This process led to a ranking of the 10 best markers of PSC, based on the data-mining method and the genes’ association with one or more of the three PSC symptoms.
At the top of the list is NR1H4, also called FXR, which ranks most highly with biliary fibrosis and biliary stasis. NR1H4 is already a clear target for cholestatic and fatty liver diseases, the authors noted. The other genes, in descending order of relevance, are: ABCB4, ABCB11, TGFB1, IFNL3, PNPLA3, IL6, TLR4, GPBAR1, and IL17A. In addition, complications of PSC were significantly associated with upregulation of TNFRS12A, SOX9, ANXA2, MMP7, and LCN2.
Separately, investigation of the 525 initially identified genes in mouse models of PSC revealed that NR0B2 is also a key player in the pathogenesis of PSC.
"NR0B2 was upregulated in PSC livers independent of gender, age, and body mass index,” the authors reported. “Importantly, it was not dependent on the severity of PSC in the prognostic cohort, suggesting that this may be an early event during the disease.”
The researchers also found a possible pathway explaining the autoimmunity of PSC – the involvement of CD274, also known as the PDL1 immune checkpoint. The authors noted that the PDL1 inhibitor pembrolizumab has previously been reported as a cause of sclerosing cholangitis.
Further, the researchers discovered overexpression of FOXP3 in the livers of patients with PSC. Because FOXP3 determines what T-cell subtypes look like, the finding suggests that an “imbalance between Foxp3þ regulatory T cells and Th17 cells may be involved in IBD and PSC,” they wrote.
Also of note was the overexpression of SOX9 in the livers of patients with PSC whose profiles suggested the worst clinical prognoses.
Finally, the researchers identified three genes as potentially involved in development of cholangiocarcinoma: GSTA3, ID2 (which is overexpressed in biliary tract cancer), and especially TMEM45A, a protein in cells’ Golgi apparatus that is already known to be involved in the development of several other cancers.
The research was funded by the French National Institute of Health and Medical Research. The authors reported no conflicts of interest.
