Small genetic variations that alter gene activity could play a role in the development of scleroderma and open new avenues for treating the disorder, a study indicates.
Many of the genes identified through this work also show unusual levels of activity in tissues often affected in this disease.
The study, “eQTL analysis in systemic sclerosis identifies new candidate genes associated with multiple aspects of disease pathology,” was published in the journal Arthritis & Rheumatology.
As is the case with most autoimmune diseases, the causes of scleroderma (or systemic sclerosis, SSc) are not well-understood. Genetics are presumed to play a role, but exactly how a person’s genes affect the condition remains unclear.
Gene expression (activity) refers to the extent to which different genes in cells are “turned on or off.” Differences in gene expression can have profound impacts on a cell’s activity — indeed, all cells in the body are identical genetically; it is differences in gene expression that gives rise to different types of cells (skin, liver, kidney, etc.).
Gene expression is regulated by a variety of biological factors, one of which is expression quantitative trait loci, known as eQTLs. An eQTL is a variation in the genetic code that helps to regulate the expression of one or more genes.
A team of European researchers conducted an analysis to identify eQTLs associated with SSc — according to the team, this study is the first to assess eQTLs in this disorder.
They analyzed genetic data from 333 patients of European descent, as well as from 524 age- and sex-matched controls (individuals without known autoimmune disease).
Through a series of computational analyses, the team first identified tens of thousands of eQTLs in various blood samples, then sorted through them to find eQTLs most likely to be associated with scleroderma. Notably, these eQTLs were enriched in tissues that are commonly affected in scleroderma, such as the lungs and skin, and 64 of the eQTLs were only identified in patients, suggesting they could be disease-specific.
The scientists then assessed the genes whose expression is affected by these eQTLs, termed eGenes.
“The eGenes on which expression SSc genetics have an intermediate or high impact are most likely to shed light on the complex pathology [biological processes] of this disease,” the researchers wrote.
A total of 233 eGenes were identified, many of which were expressed at significantly higher or lower levels in tissues typically affected in SSc. Most of these genes are known to be involved in processes implicated in SSc development, such as immune system alteration and fibrosis (scarring).
Next, the investigators assessed these eGenes to determine whether any of them were known targets for existing therapies, which might be repurposed to treat SSc. They identified seven genes that have been targeted in other immune-mediated diseases.
These genes “are potential candidates for study in clinical trials on SSc,” the researchers wrote.
“The data of the present study provides a new layer of the molecular complexity of SSc, contributing to a better understanding of the [development] of the disease,” they concluded.
Researchers noted several limitations to their study, including the fact that they did not distinguish between types of SSc (limited or diffuse), did not have access to data on self-targeting antibodies, and the technologies used to identify eQTLs have their own limitations.
As such, they said additional studies are needed to confirm and expand their findings.
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