A large-scale DNA analysis in different tissues revealed an association between scleroderma and groups of genes driving well-known inflammation pathways.
This approach helps explain the complex interplay between the diverse genes associated with scleroderma development. It also shows potential to lead to targeted and effective therapies, the investigators said.
The study, “Analysis of gene expression profiles and protein-protein interaction networks in multiple tissues of systemic sclerosis,” was published in the journal BMC Medical Genomics.
Scleroderma involves multiple organs, including the skin, lungs, heart, kidneys, and the intestinal tract. While both genetic and environmental factors are regarded as contributing to scleroderma, how the disease develops remains unknown.
Traditionally, researchers have searched for a particular gene or protein that leads to scleroderma. However, recent studies have suggested a more complex scenario in which multiple genes interacting with environmental factors play an important role.
DNA microarray analysis enables the simultaneous examination of large numbers of genes. In this technique, messenger RNA (mRNA) — derived from DNA and containing information to make proteins — is first isolated from tissues and loaded onto tiny spots on a slide (chip). After mRNA is converted to DNA, colored probes are used to identify which genes are more or less active as compared with a reference (control) sample.
Using this technique, the pattern of gene activity, or gene expression, is then assessed to identify which genes are associated with a given disease.
This approach was used by investigators in Iran to identify multiple genes connected to scleroderma.
Skin and lung tissue, as well as peripheral blood mononuclear cells (PBMCs) — which include immune B-cells, T-cells, and macrophages — from scleroderma patients were compared with healthy tissue and cells to identify genes with altered expression, or differentially expressed genes (DEGs). The researchers then mapped these genes to find potential interactions with different tissues.
The data were then refined to describe groups of interacting genes, called clusters, associated with scleroderma. Each of these clusters described the link between specific genes that underlie disease development.
In skin tissue from scleroderma patients, a total of 119 DEGs were found. After review, four disease-associated clusters of interacting genes were identified. Likewise, 619 DEGs from lung tissue were found in 12 clusters. In PBMCs, the analysis revealed 52 DEGs in 2 clusters.
Skin, lung, and PBMCs showed enhanced genetic interactions in the tumor necrosis factor (TNF) signaling pathway, a well-known driver of inflammation.
Additional clusters linked to immunity and inflammation, which were seen in all three tissue types, also were identified. However, clusters related to fibrosis (scarring) were found only in skin and lung tissues.
“Based on the current results, it seems that common pathological pathways contribute to the pathogenesis of SSc [scleroderma] in different tissues,” the scientists said.
“Ultimately, sampling from diverse patients should be conducted tissue by tissue in different stages of the disease to perform more accurate tissue comparisons and design effective systemic or targeted therapies for SSc in the future,” they said.
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