Bioinformatic analysis finds genes with potential role in SSc
Four genes could be biomarkers, treatment targets for systemic sclerosis
An analysis of genetic data from patient skin samples revealed four genes that may be involved in the development or progression of systemic sclerosis (SSc), as well as regulatory molecules that also might contribute.
The scientists believe these four genes — SERPINE1, CCL2, IL6, and ISG15 — could be potential treatment targets for SSc, although more research is needed “to further validate our conclusion,” the authors wrote.
The study, “Bioinformatics-integrated screening of systemic sclerosis-specific expressed markers to identify therapeutic targets,” was published in the journal Frontiers in Immunology.
Given its complexity, there is not yet an approved therapy to target the underlying cause of SSc. That’s why there is a need to better understand its underlying mechanisms and identify new treatments
Bioinformatic analysis of published genetic data has become a popular way of identifying genes that might play a role in various diseases. Such genes and the proteins they are responsible for producing could serve as disease biomarkers and therapeutic targets.
In the study, researchers in China performed bioinformatic analysis using genetic information obtained from skin samples of SSc patients and healthy people that were contained across four published datasets.
They identified hundreds of genes with different activity, or expression, in SSc samples compared with healthy people; many were found in blood/immune tissues or bone/muscle tissues.
The most common biological roles for these genes were related to regulation of the actin cytoskeleton, which provides cells with structural and mobility support, as well as immune and other metabolic processes.
A series of additional analyses narrowed the search to six genes that were altered most significantly in the SSc samples. Of them, four were more highly expressed in SSc samples than in healthy people: SERPINE1, CCL2, IL6, and ISG15.
SERPINE1 provides instructions to produce plasminogen activator inhibitor-1 (PAI-1), which is involved in blood clotting and tissue fibrosis (scarring). CCL2, IL6, and ISG15 each have been implicated in immune and inflammatory processes.
“Thus, SERPINE1, CCL2, IL6, and ISG15 may be effective biomarkers for SSc,” the researchers wrote, annotating these genes of interest as “hub genes.”
That finding was confirmed in a mouse SSc model, where the genes again were found to have higher expression compared with healthy mice. The protein that each gene was responsible for producing also was elevated in the SSc model.
It ultimately was determined that SERPINE1 had the best diagnostic value as an SSc biomarker, with the ability to distinguish SSc samples from healthy ones with nearly 95% accuracy.
Further bioinformatic analysis identified a handful of regulatory molecules involved in modulating these SSc genes of interest, which also might be related to the disease’s onset or progression.
Because the SSc hub genes could play a role in SSc progression, and thus may be treatment targets, the team conducted an analysis to identify whether any existing medications or molecules might interact with them.
Three medications were identified that could hold the most significant potential for SSc: carlumab, bindarit, and aleplasinin.
Carlumab is an antibody that specifically targets CCL2, the immune-signaling protein that CCL2 produces, whereas bindarit inhibits production of CCL2. Aleplasinin is a small molecule inhibitor of SERPINE1‘s protein product, PAI-1.
‘Shedding new light on SSc pathogenesis’
Overall, the study identifies potential SSc biomarker genes, their regulators, and molecules that target them, “shedding new light on SSc pathogenesis [disease mechanisms],” the researchers wrote.
“We anticipate that the present findings will highlight the importance of combining PAI-1 and inflammatory factors in the therapy and diagnosis of SSc,” the team concluded.